U.S. patent application number 12/675065 was filed with the patent office on 2011-02-24 for 17beta-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of hormone-related diseases.
This patent application is currently assigned to UNIVERSITAT DES SAARLANDES. Invention is credited to Emmanuel Bey, Martin Frotscher, Rolf Hartmann, Sandrine Oberwinkler.
Application Number | 20110046147 12/675065 |
Document ID | / |
Family ID | 39929888 |
Filed Date | 2011-02-24 |
United States Patent
Application |
20110046147 |
Kind Code |
A1 |
Hartmann; Rolf ; et
al. |
February 24, 2011 |
17BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1 INHIBITORS FOR THE
TREATMENT OF HORMONE-RELATED DISEASES
Abstract
The invention relates to 17beta-hydroxysteroid dehydrogenase
type 1 (17betaHSD1) inhibitors, the preparation thereof and the use
thereof for the treatment and prophylaxis of hormone-related,
especially estrogen-related or androgen-related, diseases.
Inventors: |
Hartmann; Rolf;
(Saarbrucken, DE) ; Frotscher; Martin; (Sulzbach,
DE) ; Oberwinkler; Sandrine; (Blieskastel, DE)
; Bey; Emmanuel; (Forbach, FR) |
Correspondence
Address: |
Briscoe, Kurt G.;Norris McLaughlin & Marcus, PA
875 Third Avenue, 8th Floor
New York
NY
10022
US
|
Assignee: |
UNIVERSITAT DES SAARLANDES
Saarbrucken
DE
|
Family ID: |
39929888 |
Appl. No.: |
12/675065 |
Filed: |
August 22, 2008 |
PCT Filed: |
August 22, 2008 |
PCT NO: |
PCT/EP08/61033 |
371 Date: |
April 1, 2010 |
Current U.S.
Class: |
514/252.1 ;
514/183; 514/277; 514/359; 514/363; 514/364; 514/365; 514/374;
514/378; 514/392; 514/399; 514/406; 514/438; 544/179; 544/336;
546/344; 548/128; 548/131; 548/203; 548/235; 548/247; 548/256;
548/325.1; 548/343.5; 548/377.1; 549/78 |
Current CPC
Class: |
A61K 31/426 20130101;
A61K 31/421 20130101; A61K 31/425 20130101; A61P 5/24 20180101;
A61K 31/40 20130101; A61K 31/53 20130101; A61K 31/535 20130101;
A61K 31/495 20130101; A61K 31/39 20130101; C07D 333/06 20130101;
A61K 31/4245 20130101; A61K 31/505 20130101; A61K 31/42 20130101;
A61P 43/00 20180101; A61K 31/4164 20130101; C07D 261/08 20130101;
C07D 231/12 20130101; A61K 31/341 20130101; A61K 31/41 20130101;
C07D 277/22 20130101; A61K 31/381 20130101; A61P 35/00 20180101;
A61K 31/433 20130101; C07D 233/54 20130101; A61P 15/00 20180101;
A61K 31/44 20130101; A61K 31/415 20130101; C07D 263/32
20130101 |
Class at
Publication: |
514/252.1 ;
514/392; 548/325.1; 548/343.5; 514/399; 548/235; 514/374;
548/377.1; 514/406; 548/247; 514/378; 548/256; 514/359; 548/203;
514/365; 549/78; 514/438; 548/131; 514/364; 548/128; 514/363;
546/344; 514/277; 544/336; 544/179; 514/183 |
International
Class: |
A61K 31/4965 20060101
A61K031/4965; A61K 31/4174 20060101 A61K031/4174; C07D 233/84
20060101 C07D233/84; C07D 233/64 20060101 C07D233/64; C07D 263/32
20060101 C07D263/32; A61K 31/421 20060101 A61K031/421; C07D 231/12
20060101 C07D231/12; A61K 31/415 20060101 A61K031/415; C07D 261/08
20060101 C07D261/08; A61K 31/42 20060101 A61K031/42; C07D 249/04
20060101 C07D249/04; A61K 31/4192 20060101 A61K031/4192; C07D
277/24 20060101 C07D277/24; A61K 31/426 20060101 A61K031/426; C07D
333/16 20060101 C07D333/16; A61K 31/381 20060101 A61K031/381; C07D
271/06 20060101 C07D271/06; A61K 31/4245 20060101 A61K031/4245;
C07D 285/08 20060101 C07D285/08; A61K 31/4196 20060101
A61K031/4196; C07D 211/00 20060101 C07D211/00; A61K 31/435 20060101
A61K031/435; C07D 241/12 20060101 C07D241/12; C07D 257/08 20060101
C07D257/08; A61K 31/395 20060101 A61K031/395; A61P 5/24 20060101
A61P005/24; A61P 35/00 20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 25, 2007 |
DE |
102007040243.2 |
Claims
1. A method of preventing or treating a hormone-related disease in
a patient in need of such treatment, said method comprising
administering to said patient an amount effective to treat said
disease of a compound of formula (I): ##STR00141## wherein n is an
integer selected from 0, 1 and 2; A is C or N; X is selected from
CH, S, N, NH, --HC.dbd.N--, --N.dbd.CH-- and O; Y is selected from
CH, --HC.dbd.CH--, S, N, O, NH and C.dbd.S; Z is selected from CH,
--HC.dbd.CH--, N, NH and O; R are independently selected from
halogen, hydroxy, --CN, --NO.sub.2, --N(R').sub.2, --SR', alkyl,
haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, --SO.sub.3R',
--NHSO.sub.2R', --R''--NHSO.sub.2R', --SO.sub.2NHR',
--R''--SO.sub.2NHR', --NHCOR', --CONHR', --R''--NHCOR',
--R''--CONHR', --COOR', --OOCR', --R''--COOR', --R''--OOCR',
--CHNR', --SO.sub.2R' and --SOR', in which one of the radicals R is
in a meta position and the other of the radicals R is in a meta or
para position relative to the linkage with the central (hetero)aryl
group; R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 independently
have the meaning as stated for R or are H; R' is selected from H,
alkyl, aryl and heteroaryl; R'' is selected from alkylene, arylene
and heteroarylene; wherein said alkyl, alkylene, aryl, arylene,
heteroaryl and heteroarylene radicals in R, R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R' and R'' may be substituted with 1 to
5 radicals R''' and wherein the radicals R''' are independently
selected from halogen, hydroxy, --CN, alkyl, alkoxy, halogenated
alkyl, halogenated alkoxy, --SH, alkylsulfanyl, arylsulfanyl, aryl,
heteroaryl, --COOH, --COOalkyl, --CH.sub.2OH, --NO.sub.2 and
--NH.sub.2; or a pharmacologically acceptable salt thereof.
2. The method according to claim 1, wherein (i) n is 1, A is N, X
is CH, Y is C.dbd.S and Z is NH; or (ii) n is 1, A is N, X is CH, Y
is CH and Z is N; or (iii) n is 1, A is C, X is O or NH, Y is CH
and Z is N; or (iv) n is 1, A is C, X is N, Y is O and Z is CH; or
(v) n is 1, A is C, X is CH, Y is O and Z is N; or (vi) n is 1, A
is C, X is S, Y is N or CH and Z is CH; or (vii) n is 1, A is C, X
is N or CH, Y is S and Z is CH; or (viii) n is 0, A is C, Y is S
and Z is --HC.dbd.CH--; or (ix) n is 1, A is C, X is CH, Y and Z
are N and NH; or (x) n is 1, A is C, X is S or O, Y and Z are N; or
(xi) n is 1, A is C, X and Z are N and Y is S; or (xii) n is 2, A
is C, X are CH, Y and Z are CH; or (xiii) n is 1, A is C, X and Y
are CH and Z is --HC.dbd.CH--; or (xiv) n is 1, A is C, X is
--N.dbd.CH--, Y is CH and Z is CH or N; or (xv) n is 2, and X, Y
and Z are N.
3. The method according to claim 1, wherein (i) the radicals R are
independently selected from halogen, hydroxy, --CN, --NO.sub.2,
--SH, --NHR', --SO.sub.3R', alkyl, haloalkyl, alkoxy, haloalkoxy,
alkylsulfanyl, aryl, heteroaryl, arylsulfanyl, --NHSO.sub.2R',
--R''--NHSO.sub.2R', --SO.sub.2NHR', --R''--SO.sub.2NHR', --NHCOR',
--CONHR', --R''--NHCOR', --R''--CONHR', --COOR', --OOCR',
--R''--COOR', --R''--OOCR', --CHNR', --SO.sub.2R' and --SOR'
(wherein R' is H, lower alkyl or phenyl and R'' is lower alkylene
or phenylene); and/or (ii) the radicals R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.5 are independently selected from H, halogen,
hydroxy, --CN, lower alkyl, halogenated lower alkyl, lower alkoxy,
(lower alkyl)sulfanyl, aryl, heteroaryl, arylsulfanyl,
--NHSO.sub.2R', --SO.sub.2NHR', --NHCOR', --CONHR', --COOR',
--OOCR', --SO.sub.2R' and --SOR' (wherein R' is H, lower alkyl or
phenyl).
4. The method according to claim 1, wherein (i) the central
aromatic ring in formula (I) is selected from a thiophene,
thiazole, thiadiazole, benzene, pyridine and tetrazine ring; and/or
(ii) R are independently selected from halogen, hydroxy, --CN,
--COOH, --NO.sub.2, --NH.sub.2, --SH, --SO.sub.3H,
SO.sub.2NH.sub.2, --NHSO.sub.2-(lower alkyl), lower alkyl,
halogenated lower alkyl, lower alkoxy and halogenated lower alkoxy;
and/or (iii) R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are
independently selected from H, halogen, halogenated lower alkyl and
lower alkyl.
5. The method according to claim 1, wherein the compound of formula
(I) is selected from,
4-(3-hydroxyphenyl)-1-(4-hydroxyphenyl)-1,3-dihydroimidazole-2-thione
(1);
4-(4-hydroxyphenyl)-1-(3-hydroxyphenyl)-1,3-dihydroimidazole-2-thion-
e (2); 3-[1-(4-hydroxyphenyl)-1H-imidazole-4-yl]phenol (4);
3-[4-(4-hydroxyphenyl)-1H-imidazole-4-yl]phenol (5);
3-[5-(4-hydroxyphenyl)-1,3-oxazole-2-yl]phenol (8);
3-[4-(4-hydroxyphenyl)-1,3-oxazole-2-yl]phenol (9);
3-[2-(4-hydroxyphenyl)-1H-imidazole-5-yl]phenol (10);
3-[5-(4-hydroxyphenyl)-1H-imidazole-2-yl]phenol (11);
3-[3-(4-hydroxyphenyl)-1H-pyrazole-5-yl]phenol (14);
3-[5-(4-hydroxyphenyl)-1H-pyrazole-3-yl]phenol (15);
3-[5-(4-hydroxyphenyl)isoxazole-3-yl]phenol (17);
3-[3-(4-hydroxyphenyl)isoxazole-5-yl]phenol (18);
3-[5-(4-hydroxyphenyl)-1,3-thiazole-2-yl]phenol (19);
3-[2-(4-hydroxyphenyl)-1,3-thiazole-5-yl]phenol (20);
3,3'-(1,3-thiazole-2,5-diyldiphenol (22);
3-[4-(4-hydroxyphenyl)-1,3-thiazole-2-yl]phenol (23);
3-[2-(4-hydroxyphenyl)-1,3-thiazole-4-yl]phenol (24);
3,3'-(1,3-thiazole-2,4-diyl)diphenol (26);
3-[3-(4-hydroxyphenyl)-2-thienyl]phenol (28);
3-[5-(4-hydroxyphenyl)-2-thienyl]phenol (29);
3,3'-thiene-2,5-diyldiphenol (31);
3-[5-(4-hydroxyphenyl)-3-thienyl]phenol (32);
3-[4-(4-hydroxyphenyl)-2-thienyl]phenol (33);
3,3'-thiene-2,4-diyldiphenol (34);
3,3'-(1,3,4-oxadiazole-2,5-diyl)diphenol (35);
3,3'-(1,3,4-thiadiazole-2,5-diyl)diphenol (36);
3,3'-(1,2,4-thiadiazole-2,5-diyl)diphenol (37);
3-[3-(4-methoxyphenyl)-1,2,4-thiadiazole-5-yl]phenol (38);
3-[3-(4-hydroxyphenyl)-1,2,4-thiadiazole-5-yl]phenol (40);
[1,1',4',1'']terphenyl-3,3'-diol (42);
[1,1',3',1'']terphenyl-4,3''-diol (43);
[1,1',4',1'']terphenyl-4,3''-diol (44);
4-[5-(3-hydroxyphenyl)-2-thienyl]-2-methylphenol (45);
4-[5-(3-hydroxyphenyl)-2-thienyl]benzene-1,2-diol (46);
2-fluoro-4-[5-(3-hydroxyphenyl)-2-thienyl]phenol (47);
2,6-difluoro-4-[5-(3-hydroxyphenyl)-2-thienyl]phenol (48);
4-[5-(3-hydroxyphenyl)-2-thienyl]-2-(trifluoromethyl)phenol (49);
3-[5-(3-fluorophenyl)-2-thienyl]phenol (50);
N-{3-[5-(3-hydroxyphenyl)-2-thienyl]phenyl}methanesulfonamide (51);
3-(5-phenyl-2-thienyl)phenol (52);
3-[5-(4-hydroxyphenyl)-2-thienyl]-5-methylphenol (53);
3-[5-(4-fluorophenyl)-2-thienyl]phenol (54);
4-[5-(3-hydroxyphenyl)-3-thienyl]-2-methylphenol (55);
4-[2-(3-hydroxyphenyl)-1,3-thiazol-5-yl]-2-methylphenol (56);
3,3'-pyridine-2,5-diyldiphenol (57); and
3,3'-(1,2,4,5-tetrazine-3,6-diyl)diphenol (59).
6. The method according to claim 1, wherein said hormone-related
disease is selected from the group consisting of (i)
estrogen-related diseases; or (ii) androgen-related diseases.
7. A compound of the formula (I) ##STR00142## wherein n is an
integer selected from 0, 1 and 2; A is C or N; X is selected from
CH, S, N, NH, --HC.dbd.N--, --N.dbd.CH-- and O; Y is selected from
CH, --HC.dbd.CH--, S, N, O, NH and C.dbd.S; Z is selected from CH,
--HC.dbd.CH--, N, NH and O; R are independently selected from
halogen, hydroxy, --CN, --NO.sub.2, --N(R').sub.2, --SR', alkyl,
haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, --SO.sub.3R',
--NHSO.sub.2R', --R''--NHSO.sub.2R', --SO.sub.2NHR',
--R''--SO.sub.2NHR', --NHCOR', --CONHR', --R''--NHCOR',
--R''--CONHR', --COOR', --OOCR', --R''--COOR', --R''--OOCR',
--CHNR', --SO.sub.2R' and --SOR', in which one of the radicals R is
in a meta position and the other of the radicals R is in a meta or
para position relative to the linkage with the central (hetero)aryl
group; R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 independently
have the meaning as stated for R or are H; R' is selected from H,
alkyl, aryl and heteroaryl; R'' is selected from alkylene, arylene
and heteroarylene; wherein said alkyl, alkylene, aryl, arylene,
heteroaryl and heteroarylene radicals in R, R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R' and R'' may be substituted with 1 to
5 radicals R'' and wherein the radicals R''' are independently
selected from halogen, hydroxy, --CN, alkyl, alkoxy, halogenated
alkyl, halogenated alkoxy, --SH, alkylsulfanyl, arylsulfanyl, aryl,
heteroaryl, --COOH, --COOalkyl, --CH.sub.2OH, --NO.sub.2 and
--NH.sub.2; with the proviso that if n is 1, A is C, X is
--N.dbd.CH--, Y is CH, Z is N, R.sup.1 to R.sup.4 are H and the
radicals R are both OH or OOCCH.sub.3, then the two radicals R are
not both in meta positions; and if n is 2, A is C, X, Y and Z are
N, R.sup.1 to R.sup.4 are H and the radicals R are both OH, then
the two radicals R are not both in meta positions; or a
pharmacologically acceptable salt thereof.
8. The compound according to claim 7, wherein (i) n is 1, A is N, X
is CH, Y is C.dbd.S and Z is NH; or (ii) n is 1, A is N, X is CH, Y
is CH and Z is N; or (iii) n is 1, A is C, X is O or NH, Y is CH
and Z is N; or (iv) n is 1, A is C, X is N, Y is O and Z is CH; or
(v) n is 1, A is C, X is CH, Y is O and Z is N; or (vi) n is 1, A
is C, X is S, Y is N or CH and Z is CH; or (vii) n is 1, A is C, X
is N or CH, Y is S and Z is CH; or (viii) n is 0, A is C, Y is S
and Z is --HC.dbd.CH--; or (ix) n is 1, A is C, X is CH, Y and Z
are N and NH; or (x) n is 1, A is C, X is S or O, Y and Z are N; or
(xi) n is 1, A is C, X and Z are N and Y is S; or (xii) n is 2, A
is C, X are CH, Y and Z are CH; or (xiii) n is 1, A is C, X and Y
are CH and Z is --HC.dbd.CH--; or (xiv) n is 1, A is C, X is
--N.dbd.CH--, Y is CH and Z is CH or N; or (xv) n is 2, and X, Y
and Z are N.
9. The compound according to claim 7, which is selected from
4-(3-hydroxyphenyl)-1-(4-hydroxyphenyl)-1,3-dihydroimidazole-2-thione
(1);
4-(4-hydroxyphenyl)-1-(3-hydroxyphenyl)-1,3-dihydroimidazole-2-thion-
e (2); 3-[1-(4-hydroxyphenyl)-1H-imidazole-4-yl]phenol (4);
3-[4-(4-hydroxyphenyl)-1H-imidazole-4-yl]phenol (5);
3-[5-(4-hydroxyphenyl)-1,3-oxazole-2-yl]phenol (8);
3-[4-(4-hydroxyphenyl)-1,3-oxazole-2-yl]phenol (9);
3-[2-(4-hydroxyphenyl)-1H-imidazole-5-yl]phenol (10);
3-[5-(4-hydroxyphenyl)-1H-imidazole-2-yl]phenol (11);
3-[3-(4-hydroxyphenyl)-1H-pyrazole-5-yl]phenol (14);
3-[5-(4-hydroxyphenyl)-1H-pyrazole-3-yl]phenol (15);
3-[5-(4-hydroxyphenyl)isoxazole-3-yl]phenol (17);
3-[3-(4-hydroxyphenyl)isoxazole-5-yl]phenol (18);
3-[5-(4-hydroxyphenyl)-1,3-thiazole-2-yl]phenol (19);
3-[2-(4-hydroxyphenyl)-1,3-thiazole-5-yl]phenol (20);
3,3'-(1,3-thiazole-2,5-diyl)diphenol (22);
3-[4-(4-hydroxyphenyl)-1,3-thiazole-2-yl]phenol (23);
3-[2-(4-hydroxyphenyl)-1,3-thiazole-4-yl]phenol (24);
3,3'-(1,3-thiazole-2,4-diyl)diphenol (26);
3-[3-(4-hydroxyphenyl)-2-thienyl]phenol (28);
3-[5-(4-hydroxyphenyl)-2-thienyl]phenol (29);
3,3'-thiene-2,5-diyldiphenol (31);
3-[5-(4-hydroxyphenyl)-3-thienyl]phenol (32);
3-[4-(4-hydroxyphenyl)-2-thienyl]phenol (33);
3,3'-thiene-2,4-diyldiphenol (34);
3,3'-(1,3,4-oxadiazole-2,5-diyl)diphenol (35);
3,3'-(1,3,4-thiadiazole-2,5-diyl)diphenol (36);
3,3'-(1,2,4-thiadiazole-2,5-diyl)diphenol (37);
3-[3-(4-methoxyphenyl)-1,2,4-thiadiazole-5-yl]phenol (38);
3-[3-(4-hydroxyphenyl)-1,2,4-thiadiazole-5-yl]phenol (40);
[1,1',4',1'']terphenyl-3,3'-diol (42);
[1,1',3',1'']terphenyl-4,3''-diol (43);
[1,1',4',1'']terphenyl-4,3''-diol (44);
4-[5-(3-hydroxyphenyl)-2-thienyl]-2-methylphenol (45);
4-[5-(3-hydroxyphenyl)-2-thienyl]benzene-1,2-diol (46);
2-fluoro-4-[5-(3-hydroxyphenyl)-2-thienyl]phenol (47);
2,6-difluoro-4-[5-(3-hydroxyphenyl)-2-thienyl]phenol (48);
4-[5-(3-hydroxyphenyl)-2-thienyl]-2-(trifluoromethyl)phenol (49);
3-[5-(3-fluorophenyl)-2-thienyl]phenol (50);
N-{3-[5-(3-hydroxyphenyl)-2-thienyl]phenyl}methanesulfonamide (51);
3-(5-phenyl-2-thienyl)phenol (52);
3-[5-(4-hydroxyphenyl)-2-thienyl]-5-methylphenol (53);
3-[5-(4-fluorophenyl)-2-thienyl]phenol (54);
4-[5-(3-hydroxyphenyl)-3-thienyl]-2-methylphenol (55);
4-[2-(3-hydroxyphenyl)-1,3-thiazol-5-yl]-2-methylphenol (56); and
3,3'-pyridine-2,5-diyldiphenol (57).
10. A medicament or pharmaceutical composition comprising at least
one compound according to claim 7 and optionally a
pharmacologically suitable carrier.
11. The medicament or pharmaceutical composition according to claim
10, which is adapted for the treatment and prophylaxis of
hormone-related, estrogen-related or androgen-related diseases.
12. The medicament or pharmaceutical composition according to claim
11, wherein said estrogen-related diseases are selected from
endometriosis, endometrial carcinoma, adenomyosis and breast
cancer.
13. The medicament or pharmaceutical composition according to claim
11, wherein said androgen-related diseases are selected from
prostate carcinoma and benign prostate hyperplasia.
14. A process for preparing the compound according to claim 7, said
comprising conducting a reaction according to the following
reaction scheme: ##STR00143## wherein the variables have the
meanings as stated in claim 7.
15. (canceled)
16. The method according to claim 1, wherein said hormone-related
disease is selected from the group consisting of estrogen-related
diseases.
Description
[0001] The invention relates to 17beta-hydroxysteroid dehydrogenase
type 1 (17betaHSD1) inhibitors, the preparation thereof and the use
thereof for the treatment and prophylaxis of hormone-related,
especially estrogen related or androgen-related, diseases.
BACKGROUND OF THE INVENTION
[0002] Steroid hormones are important chemical carriers of
information serving for the long-term and global control of
cellular functions. They control the growth and the differentiation
and function of many organs. However, in addition to such
physiological functions, they also have negative effects: they may
favor the pathogenesis and proliferation of diseases in the
organism, such as mammary and prostate cancers (Deroo, B. J. et
al., 3. Clin. Invest., 116: 561-570 (2006); Fernandez, S. V. et
al., Int. 3. Cancer, 118: 1862-1868 (2006)).
[0003] Within the scope of the biosynthesis of steroids, sex
hormones are produced in the testes or ovaries. In contrast, the
production of glucocorticoids and mineral corticoids takes place in
the adrenal glands. Moreover, individual synthetic steps also occur
outside the glands, namely in the brain or in the peripheral
tissue, e.g., adipose tissue (Bulun, S. E. et al., 3. Steroid
Biochem. Mol. Biol., 79: 19-25 (2001); Gangloff, A. et al.,
Biochem. J., 356: 269-276 (2001)). In this context, Labrie coined
the term "intracrinology" in 1988 (Labrie, C. et al.,
Endocrinology, 123: 1412-1417 (1988); Labrie, F. et al., Ann.
Endocrinol. (Paris), 56: 23-29 (1995); Labrie, F. et al., Harm.
Res., 54: 218-229 (2000)). Attention was thus focused on the
synthesis of steroids that are formed locally in peripheral tissues
and also display their action there without getting into the blood
circulation. The intensity of the activity of the hormones is
modulated in the target tissue by means of various enzymes.
[0004] Thus, it could be shown that the 17.beta.-hydroxysteroid
dehydrogenase type 1 (17.beta.-HSD1), which catalyzes the
conversion of estrone to estradiol, is more abundant in
endometriotic tissue and breast cancer cells while there is a
deficiency in 17.beta.-HSD type 2, which catalyzes the reverse
reaction (Bulun, S. E. et al., J. Steroid Biochem. Mol. Biol., 79:
19-25 (2001); Miyoshi, Y. et al., Int. J. Cancer, 94; 685-689
(2001)).
[0005] A major class of steroid hormones is formed by the
estrogens, the female sex hormones, whose biosynthesis takes place
mainly in the ovaries and reaches its maximum immediately before
ovulation. However, estrogens also occur in the adipose tissue,
muscles and some tumors. Their main functions include a genital
activity, i.e., the development and maintenance of the female
sexual characteristics as well as an extragenital lipid-anabolic
activity leading to the development of subcutaneous adipose tissue.
In addition, they are involved in the pathogenesis and
proliferation of estrogen-related diseases, such as endometriosis,
endometrial carcinoma, adenomyosis and breast cancer (Bulun, S. E.
et al., 3. Steroid Biochem. Mol. Biol., 79: 19-25 (2001); Miyoshi,
Y. et al., Int. J. Cancer, 94: 685-689 (2001); Gunnarsson, C. et
al., Cancer Res., 61: 8448-8451 (2001); Kitawaki, J. Journal of
Steroid Biochemistry & Molecular Biology, 83: 149-155 (2003);
Vihko, P. et al., J. Steroid. Biochem. Mol. Biol., 83: 119-122
(2002); Vihko, P. et al., Mol. Cell. Endocrinol., 215: 83-88
(2004)).
[0006] The most potent estrogen is estradiol (E.sub.2), which is
formed in premenopausal females, mainly in the ovaries. On an
endocrine route, it arrives at the target tissues, where it
displays its action by means of an interaction with the estrogen
receptor (ER) .alpha.. After the menopause, the plasma E.sub.2
level decreases to 1/10 of the estradiol level found in
premenopausal females (Santner, S. J. et al., J. Clin. Endocrinol.
Metab., 59: 29-33 (1984)). E.sub.2 is mainly produced in the
peripheral tissue, e.g., breast tissue, endometrium, adipose tissue
and skin, from inactive precursors, such as estrone sulfate
(E.sub.1-S), dehydroepiandrosterone (DHEA) and DHEA-S. These
reactions occur with the participation of various steroidogenic
enzymes (hydroxysteroid dehydrogenases, aromatase), which are in
part more abundantly produced in the peripheral tissue, where these
active estrogens display their action. As a consequence of such
intracrine mechanism for the formation of E.sub.2, its
concentration in the peripheral tissue, especially in
estrogen-related diseases, is higher than that in the healthy
tissue. Above all, the growth of many breast cancer cell lines is
stimulated by a locally increased estradiol concentration. Further,
the occurrence and progress of diseases such as endometriosis,
leiomyosis, adenomyosis, menorrhagia, metrorrhagia and dysmenorrhea
is dependent on a significantly increased estradiol level in
accordingly diseased tissue.
[0007] Endometriosis is an estrogen-related disease afflicting
about 5 to 10% of all females of childbearing age (Kitawaki, J.,
Journal of Steroid Biochemistry & Molecular Biology, 83:
149-155 (2003)). From 35 to 50% of the females suffering from
abdominal pain and/or sterility show signs of endometriosis (Urdl,
W., J. Reproduktionsmed. Endokrinol., 3: 24-30 (2006)). This
diseases is defined as a histologically detected ectopic
endometrial glandular and stromal tissue. In correspondingly severe
cases, this chronic disease, which tends to relapse, leads to pain
of different intensities and variable character and possibly to
sterility. Three macroscopic clinical pictures are distinguished:
peritoneal endometriosis, retroperitoneal deep-infiltrating
endometriosis including adenomyosis uteri, and cystic ovarial
endometriosis. There are various explanatory theories for the
pathogenesis of endometriosis, e.g., the metaplasia theory, the
transplantation theory and the theory of autotraumatization of the
uterus as established by Leyendecker (Leyendecker, G. et al., Hum.
Reprod., 17: 2725-2736 (2002)).
[0008] According to the metaplasia theory (Meyer, R., Zentralbl.
Gynakol., 43: 745-750 (1919); Nap, A. W. et al., Best Pract. Res.
Clin. Obstet. Gynaecol., 18: 233-244 (2004)), pluripotent coelomic
epithelium is supposed to have the ability to differentiate and
form endometriotic foci even in adults under certain conditions.
This theory is supported by the observation that endometrioses, in
part severe ones, can occur in females with lacking uterus and
gynastresy. Even in males who were treated with high estrogen doses
due to a prostate carcinoma, an endometriosis could be detected in
singular cases.
[0009] According to the theory postulated by Sampson (Halme, J. et
al., Obstet. Gynecol., 64: 151-154 (1984); Sampson, J., Boston Med.
Surg. J., 186: 445-473 (1922); Sampson, J., Am. J. Obstet.
Gynecol., 14: 422-469 (1927)), retrograde menstruation results in
the discharge of normal endometrial cells or fragments of the
eutopic endometrium into the abdominal cavity with potential
implantation of such cells in the peritoneal space and further
development to form endometriotic foci. Retrograde menstruation
could be detected as a physiological event. However, not all
females with retrograde menstruation become ill with endometriosis,
but various factors, such as cytokines, enzymes, growth factors,
play a critical role.
[0010] The enhanced autonomous non-cyclical estrogen production and
activity as well as the reduced estrogen inactivation are typical
peculiarities of endometriotic tissue. This enhanced local estrogen
production and activity is caused by a significant overexpression
of aromatase, expression of 17.beta.-HSD1 and reduced inactivation
of potent E2 due to a lack of 17.beta.-HSD2, as compared to the
normal endometrium (Bulun, S. E. et al., J. Steroid Biochem. Mol.
Biol., 79: 19-25 (2001); Kitawaki, J., Journal of Steroid
Biochemistry & Molecular Biology, 83: 149-155 (2003); Karaer,
O. et al., Acta. Obstet. Gynecol. Scand., 83: 699-706 (2004);
Zeitoun, K. et al., J. Clin. Endocrinol. Metab., 83: 4474-4480
(1998)).
[0011] The polymorphic symptoms caused by endometriosis include any
pain symptoms in the minor pelvis, back pain, dyspareunia, dysuria
and defecation complaints.
[0012] One of the therapeutic measures employed most frequently in
endometriosis is the surgical removal of the endometriotic foci
(Urdl, W., J. Reproduktionsmed. Endokrinol., 3: 24-30 (2006)).
Despite new therapeutic concepts, medicamental treatment remains in
need of improvement. The purely symptomatic treatment of
dysmenorrhea is effected by means of non-steroidal
anti-inflammatory drugs (NSAID), such as acetylsalicylic acid,
Indomethacine, ibuprofen and diclofenac. Since a COX2
overexpression could be observed both in malignant tumors and in
the eutopic endometrium of females with endometriosis, a therapy
with the selective COX2 inhibitors, such as celecoxib, suggests
itself (Fagotti, A. et al., Hum. Reprod. 19: 393-397 (2004); Hayes,
E. C. et al., Obstet. Gynecol. Surv., 57: 768-780 (2002)). Although
they have a better gastro-intestinal side effect profile as
compared to the NSAID, the risk of cardiovascular diseases,
infarction and stroke is increases, especially for patients with a
predamaged cardiovascular system (Dogne, J. M. et al., Curr. Pharm.
Des., 12: 971-975 (2006)). The causal medicamental therapy is based
on estrogen deprivation with related variable side effects and a
generally contraceptive character. The gestagens with their
anti-estrogenic and antiproliferative effect on the endometrium
have great therapeutic significance. The most frequently employed
substances include medroxyprogesterone acetate, norethisterone,
cyproterone acetate. The use of danazole is declining due to its
androgenic side effect profile with potential gain of weight,
hirsutism and acne. The treatment with GnRH analogues is of key
importance in the treatment of endometriosis (Rice, V.; Ann. NY
Acad. Sci., 955: 343-359 (2001)); however, the duration of the
therapy should not exceed, a period of 6 months since a longer term
application is associated with irreversible damage and an increased
risk of fracture. The side effect profile of the GnRH analogues
includes hot flushes, amenorrhea, loss of libido and osteoporosis,
the latter mainly within the scope of a long term treatment.
[0013] Another therapeutic approach involves the steroidal and
non-steroidal aromatase inhibitors. It could be shown that the use
of the non-steroidal aromatase inhibitor letrozole leads to a
significant reduction of the frequency and severity of dysmenorrhea
and dyspareunia and to a reduction of the endometriosis marker
CA125 level (Soysal, S. et al., Hum. Reprod., 19: 160-167 (2004)).
The side effect profile of aromatase inhibitors ranges from hot
flushes, nausea, fatigue to osteoporosis and cardiac diseases. Long
term effects cannot be excluded.
[0014] All the possible therapies mentioned herein are also
employed in the combatting of diseases such as leiomyosis,
adenomyosis, menorrhagia, metrorrhagia and dysmenorrhea.
[0015] Every fourth cancer disease in the female population falls
under the category of mammary cancers. This disease is the main
cause of death in the Western female population at the age of from
35 to 54 years (Nicholls, P. J., Pharm. J., 259: 459-470 (1997)).
Many of these tumors exhibit an estrogen-dependent growth and are
referred to as so-called HDBC (hormone dependent breast cancer). A
distinction is made between ER+ and ER- tumors. The classification
criteria are important to the choice of a suitable therapy. About
50% of the breast cancer cases in premenopausal females and 75% of
the breast cancer cases in post-menopausal females are ER+
(Coulson, C., Steroid biosynthesis and action, 2nd edition, 95-122
(1994); Lower, E. et al., Breast Cancer Res. Treat., 58: 205-211
(1999)), i.e., the growth of the tumor is promoted by as low as
physiological concentrations of estrogens in the diseased
tissue.
[0016] The therapy of choice at an early stage of breast cancer is
surgical measures, if possible, breast-preserving surgery. Only in
a minor number of cases, mastectomy is performed. In order to avoid
relapses, the surgery is followed by radiotherapy, or else
radiotherapy is performed first in order to reduce a larger tumor
to an operable size. In an advanced state, or when metastases occur
in the lymph nodes, skin or brain, the objective is no longer to
heal the disease, but to achieve a palliative control thereof.
[0017] The therapy of the mammary carcinoma is dependent on the
hormone receptor status of the tumor, on the patient's hormone
status and on the status of the tumor (Paepke, S. et al.,
Onkologie, 26 Suppl., 7: 4-10 (2003)). Various therapeutical
approaches are available, but all are based on hormone deprivation
(deprivation of growth-promoting endogenous hormones) or hormone
interference (supply of exogenous hormones). However, a
precondition of such responsiveness is the endocrine sensitivity of
the tumors, which exists with HDBC ER+ tumors. The drugs employed
in endocrine therapy include GnRH analogues, anti-estrogens and
aromatase inhibitors. GnRH analogues, such as gosereline, will bind
to specific membrane receptors in the target organ, the pituitary
gland, which results in an increased secretion of FSH and LH. These
two hormones in turn lead to a reduction of GnRH receptors in a
negative feedback loop in the pituitary cells. The resulting
desensitization of the pituitary cells towards GnRH leads to an
inhibition of FSH and LH secretion, so that the steroid hormone
feedback loop is interrupted. The side effects of such therapeutic
agents include hot flushes, sweats and osteoporosis.
[0018] Another therapeutic option is the use of anti-estrogens,
antagonists at the estrogen receptor. Their activity is based on
the ability to competitively bind to the ER and thus avoid the
specific binding of the endogenous estrogen. Thus, the natural
hormone is no longer able to promote tumor growth. Today,
therapeutic use involves so-called SERM (selective estrogen
receptor modulators), which develop estrogen agonism in tissues
such as bones or liver, but have antagonistic and/or minimal
agonistic effects in breast tissue or uterus (Holzgrabe, U., Pharm.
Unserer Zeit, 33: 357-359 (2004); Pasqualini, J. R., Biochim.
Biophys. Acta., 1654: 123-143 (2004); Sexton, M. J. et al., Prim
Care Update Ob Gyns, 8: 25-30 (2001)). Thus, these compounds are
not only effective in combatting breast cancer, but also increase
the bone density and reduce the risk of osteoporosis in
postmenopausal females. The use of the SERM tamoxifen is most
widely spread. However, after about 12-18 months of treatment,
there is development of resistance, an increased risk of
endometrial cancers and thrombo-embolic diseases due to the partial
agonistic activity at the ER (Goss, P. E. et al., Clin. Cancer
Res., 10: 5717-5723 (2004); Nunez, N. P. et al., Clin. Cancer Res.,
10: 5375-5380 (2004)).
[0019] The enzymatically catalyzed estrogen biosynthesis may also
be influenced by selective enzyme inhibitors. The enzyme aromatase,
which converts C19 steroids to C18 steroids, was one of the first
targets for lowering the estradiol level. This enzyme complex,
which belongs to the cytochrome P-450 enzymes, catalyzes the
aromatization of the androgenic A ring to form estrogens. The
methyl group at position 10 of the steroid is thereby cleaved off.
The first aromatase inhibitor employed for the therapy of breast
cancer was aminogluthetimide. However, aminogluthetimide affects
several enzymes of the cytochrome P-450 superfamily and thus
inhibits a number of other biochemical conversions. For example,
among others, the compound interferes with the steroid production
of the adrenal glands so heavily that a substitution of both
glucocorticoids and mineral corticoids may be necessary. In the
meantime, more potent and more selective aromatase inhibitors,
which can be subdivided into steroidal and non-steroidal compounds,
are on the market. The steroidal inhibitors include, for example,
exemestane, which has a positive effect on the bone density, which
is associated with its affinity for the androgen receptor (Goss, P.
E. et al., Clin. Cancer Res., 10: 5717-5723 (2004)). However, this
type of compounds are irreversible inhibitors that also have a
substantial number of side effects, such as hot flushes, nausea,
fatigue. However, there are also non-steroidal compounds that are
employed therapeutically, for example, letrozole. The advantage of
these compounds resides in the lesser side effects, they do not
cause uterine hypertrophy, but have no positive effect on the bone
density and result in an increase of LDL (low density lipoprotein),
cholesterol and triglyceride levels (Goss, P. E. et al., Clin.
Cancer Res., 10: 5717-5723 (2004); Nunez, N. P. et al., Clin.
Cancer Res., 10: 5375-5380 (2004)). Today, aromatase inhibitors are
predominantly employed as second-line therapeutic agents. In the
meantime, however, the equivalence or even superiority of aromatase
inhibitors to SERM, such as tamoxifene, has been proven in clinical
studies (Geisler, J. et al., Crit. Rev. Oncol. Hematol., 57: 53-61
(2006); Howell, A. et al., Lancet, 365: 60-62 (2005)). Thus, the
use of aromatase inhibitors also as first-line therapeutical agents
is substantiated.
[0020] However, the estrogen biosynthesis in the peripheral tissue
also includes other pathways for the production of E1 and the more
potent E2 by avoiding the enzyme aromatase that is locally present
in the target tissue, for example, breast tumors. Two pathways for
the production of estrogens in breast cancer tissue are postulated
(Pasqualini, J. R., Biochim. Biophys. Acta., 1654: 123-143 (2004)),
the aromatase pathway (Abul-Hajj, Y. J. et al., Steroids, 33:
205-222 (1979); Lipton, A. et al., Cancer, 59: 779-782 (1987)) and
the sulfatase pathway (Perel, E. et al., J. Steroid. Biochem., 29:
393-399 (1988)). The aromatase pathway includes the production of
estrogens from androgens with participation of the enzyme
aromatase. The sulfatase pathway is the pathway for the production
of estrone/estradiol by means of the enzyme steroid sulfatase, an
enzyme that catalyzes the conversion of estrone sulfate and DHEA-S
to estrone and DHEA. In this way, 10 times as much estrone is
formed in the target tissue as compared to the aromatase pathway
(Santner, S. J. et al., J. Clin. Endocrinol. Metab., 59: 29-33
(1984)). The estrone is then reduced by means of the enzyme
17.beta.-HSD1 to form E2, the most potent estrogen. Steroid
sulfatase and 17.beta.-HSD1 are new targets in the battle against
estrogen-related diseases, especially for the development of
therapeutic agents for mammary carcinomas (Pasqualini, J. R.,
Biochim. Biophys. Acta., 1654: 123-143 (2004)).
[0021] Numerous steroidal sulfatase inhibitors could be found,
including the potent irreversible inhibitor EMATE, which exhibited
an agonistic activity at the estrogen receptor, however (Ciobanu,
L. C. et al., Cancer Res., 63: 6442-6446 (2003); Hanson, S. R. et
al., Angew. Chem. Int. Ed. Engl., 43: 5736-5763 (2004)). Some
potent non-steroidal sulfatase inhibitors could also be found, such
as COUMATE and derivatives as well as numerous sulfamate
derivatives of tetrahydronaphthalene, indanone and tetralone
(Hanson, S. R. et al., Angew. Chem. Int. Ed. Engl., 43: 5736-5763
(2004)). However, no sulfatase inhibitor has been able to enter the
therapy of estrogen-related diseases to date.
[0022] The inhibition of 17.beta.-HSD1, a key enzyme in the
biosynthesis of E2, the most potent estrogen, could suggest itself
as an option in the therapy of estrogen-related diseases in both
premenopausal and postmenopausal females (Kitawaki, J., Journal of
Steroid Biochemistry & Molecular Biology, 83: 149-155 (2003);
Allan, G. M. et al., Mol. Cell. Endocrinol., 248: 204-207 (2006);
Penning, T. M., Endocr. Rev., 18: 281-305 (1997); Sawicki, M. W. et
al., Proc. Natl. Acad. Sci. USA, 96: 840-845 (1999); Vihko, P. et
al., Mol. Cell. Endocrinol., 171: 71-76 (2001)). An advantage of
this approach is the fact that the intervention is effected in the
last step of estrogen biosynthesis, i.e., the conversion of E1 to
the highly potent E2 is inhibited. The intervention is effected in
the biosynthetic step occurring in the peripheral tissue, so that a
reduction of estradiol production takes place locally in the
diseased tissue. The use of correspondingly selective inhibitors
would probably be associated with little side effects since the
synthesis of other steroids would remain unaffected. It would be
important that such inhibitors exhibit no or only very little
agonistic activity at the ER, especially at the ER .alpha., since
agonistic binding is accompanied by an activation and thus
proliferation and differentiation of the target cell. In contrast,
an antagonistic activity of such compounds at the ER would prevent
the natural substrates from binding at the receptor and result in a
further reduction of the proliferation of the target cells. The use
of selective 17.beta.-HSD1 inhibitors for the therapy of numerous
estrogen-dependent diseases is discussed, for example, for breast
cancer, tumors of the ovaries, prostate carcinoma, endometrial
carcinoma, endometriosis, adenomyosis. Highly interesting and
completely novel is the proposal to employ selective inhibitors of
17.beta.-HSD1 for prevention when there is a genetic disposition
for breast cancer (Miettinen, M. et al., J. Mammary Gland. Biol.
Neoplasia, 5: 259-270 (2000)).
[0023] Hydroxysteroid dehydrogenases (HSD) can be subdivided into
different classes. The 11.beta.-HSD modulate the activity of
glucocorticoids, 3.beta.-HSD catalyzes the reaction of
.DELTA.5-3.beta.-hydroxysteroids (DHEA or
5-androstene-3.beta.,17.beta.-diol) to form 5-3.beta.-ketosteroids
(androstenedione or testosterone). 17.beta.-HSD convert the less
active 17-ketosteroids to the corresponding highly active
17-hydroxy compounds (androstenedione to testosterone and E.sub.1
to E.sub.2) or conversely (Payne, A. H. et al., Endocr. Rev., 25:
947-970 (2004); Peltoketo, H. et al., J. Mol. Endocrinol., 23: 1-11
(1999); Suzuki, T. et al., Endocr. Relat. Cancer, 12: 701-720
(2005)). Thus, the HSD play a critical role in both the activation
and the inactivation of steroid hormones. Depending on the cell's
need for steroid hormones, they alter the potency of the sex
hormones (Penning, T. M., Endocr. Rev., 18: 281-305 (1997)), for
example, E.sub.1 is converted to the highly potent E.sub.2 by means
of 17.beta.-HSD1, while E.sub.2 is converted to the less potent
E.sub.1 by means of 17.beta.-HSD2; 17.beta.-HSD2 inactivates
E.sub.2 while 17.beta.-HSD1 activates E.sub.1.
[0024] To date, fourteen different 17.beta.-HSDs have been
identified (Lukacik, P. et al., Mol. Cell. Endocrinol., 1: 61-71
(2006)), and twelve of these enzymes could be cloned (Suzuki, T. et
al., Endocr. Relat. Cancer, 12: 701-720 (2005)). They all belong to
the so-called short chain dehydrogenase/reductase (SDR) family,
with the exception of 17.beta.-HSD5, which is a ketoreductase. The
amino acid identity between the different 17.beta.-HSDs is as low
as 20-30% (Luu-The, V., J. Steroid Biochem. Mol. Biol., 76: 143-151
(2001)). The 17.beta.-HSD family includes both membrane-bound and
soluble enzymes. The X-ray structure of 6 human subtypes is known
(1,3,5,10,11,13) (Ghosh, D. et al., Structure, 3: 503-513 (1995);
Kissinger, C. R. et al., J. Mol. Biol., 342: 943-952 (2004); Zhou,
M. et al., Acta Crystallogr. D. Biol. Crystallogr., 58: 1048-1050
(2002). The 17.beta.-HSDs are NAD(H)-dependent and
NADP(H)-dependent enzymes. They play a critical role in the
hormonal regulation in humans. The enzymes are distinguished by
their tissue distribution, catalytic preference (oxidation or
reduction), substrate specificity and subcellular localization. The
same HSD subtype was found in different tissues. It is likely that
all 17.beta.-HSDs are expressed in the different estrogen-dependent
tissues, but in different concentrations. In diseased tissue, the
ratio between the different subtypes is altered as compared to
healthy tissue, some subtypes being overexpressed while others may
be absent. This may cause an increase or decrease of the
concentration of the corresponding steroid. Thus, the 17.beta.-HSDs
play an extremely important role in the regulation of the activity
of the sex hormones. Further, they are involved in the development
of estrogen-sensitive diseases, such as breast cancer, ovarian,
uterine and endometrial carcinomas, as well as androgen-related
diseases, such as prostate carcinoma, benign prostate hyperplasia,
acne, hirsutism etc. It has been shown that some 17.beta.-HSDs are
also involved in the development of further diseases, e.g.,
pseudohermaphrodism (17.beta.-HSD3 (Geissler, W. M. et al., Nat.
Genet., 7: 34-39 (1994))), bifunctional enzyme deficiency
(17.beta.-HSD4 (van Grunsven, E. G. et al., Proc. Natl. Acad. Sci.
USA, 95: 2128-2133 (1998))), polycystic kidney diseases
(17.beta.-HSD8 (Maxwell, M. M. et al., J. Biol. Chem., 270:
25213-25219 (1995))) and Alzheimer's (17.beta.-HSD10 (Kissinger, C.
R. et al., J. Mol. Biol., 342: 943-952 (2004); He, X. Y. et al., J.
Biol. Chem., 274: 15014-15019 (1999); He, X. Y. et al., Mol. Cell.
Endocrinol., 229: 111-117 (2005); He, X. Y. et al., J. Steroid
Biochem. Mol. Biol., 87: 191-198 (2003); Yan, S. D. et al., Nature,
389: 689-695 (1997))).
[0025] The best characterized member of the 17.beta.-HSDs is the
type 1 17.beta.-HSD. The 17.beta.-HSD1 is an enzyme from the SDR
family, also referred to as human placenta estradiol dehydrogenase
(Gangloff, A. et al., Biochem. J., 356: 269-276 (2001); Jornvall,
H. et al., Biochemistry, 34: 6003-6013 (1995)). Its designation as
assigned by the enzyme commission is E.C.1.1.1.62.
[0026] Engel et al. (Langer, L. J. et al., J. Biol. Chem., 233:
583-588 (1958)) were the first to describe this enzyme in the
1950's. In the 1990's, first crystallization attempts were made, so
that a total of 16 crystallographic structures can be recurred to
today in the development of inhibitors (Alho-Richmond, S. et al.,
Mol. Cell. Endocrinol., 248: 208-213 (2006)). Available are X-ray
structures of the enzyme alone, but also of binary and ternary
complexes of the enzyme with its substrate and other ligands or
substrate/ligand and cofactor.
[0027] 17.beta.-HSD1 is a soluble cytosolic enzyme. NADPH serves as
a cofactor. 17.beta.-HSD1 is encoded by a 3.2 kb gene consisting of
6 exons and 5 introns that is converted to a 2.2 kb transcript
(Luu-The, V., J. Steroid Biochem. Mol. Biol., 76: 143-151 (2001);
Labrie, F. et al., J. Mol. Endocrinol., 25: 1-16 (2000)). It is
constituted by 327 amino acids. The molecular weight of the monomer
is 34.9 kDa (Penning, T. M., Endocr. Rev., 18; 281-305 (1997)).
[0028] 17.beta.-HSD1 is expressed in the placenta, liver, ovaries,
endometrium, prostate gland, peripheral tissue, such as adipose
tissue and breast cancer cells (Penning, T. M., Endocr. Rev., 18:
281-305 (1997)). It was isolated for the first time from human
placenta (Jarabak, J. et al., J. Biol. Chem., 237: 345-357 (1962)).
The main function of 17.beta.-HSD1 is the conversion of the less
active estrone to the highly potent estradiol. However, it also
catalyzes to a lesser extent the reaction of dehydroepiandrosterone
(DHEA) to 5-androstene-3.beta.,17.beta.-diol, an androgen showing
estrogenic activity (Labrie, F., Mol. Cell. Endocrinol., 78:
C113-118 (1991); Poirier, D., Curr. Med. Chem., 10: 453-477 (2003);
Poulin, R. et al., Cancer Res., 46: 4933-4937 (1986)). In vitro,
the enzyme catalyzes the reduction and oxidation between E.sub.1
and E.sub.2 while it catalyzes only the reduction under
physiological conditions. These bisubstrate reactions proceed
according to a random catalytic mechanism, i.e., either the steroid
or the cofactor is first to bind to the enzyme (Betz, G., J. Biol.
Chem., 246: 2063-2068 (1971)). A catalytic mechanism in which the
cofactor binds to the enzyme first is also postulated (Neugebauer,
A. et al., Bioorg. Med. Chem., submitted (2005)).
[0029] The enzyme consists of a substrate binding site and a
channel that opens into the cofactor binding site. The substrate
binding site is a hydrophobic tunnel having a high complementarity
to the steroid. The 3-hydroxy and 17-hydroxy groups in the steroid
form four hydrogen bonds to the amino acid residues His221, Glu282,
Ser142 and Tyr155. The hydrophobic van der Waals interactions seem
to form the main interactions with the steroid while the hydrogen
bonds are responsible for the specificity of the steroid for the
enzyme (Labrie, F. et al., Steroids, 62: 148-158 (1997)). Like with
all the other enzymes of this family, what is present as a cofactor
binding site is the Rossmann fold, which is a region consisting of
.alpha.-helices and sheets
(.beta.-.alpha.-.beta.-.alpha.-.beta.).sub.2, a generally occurring
motif Gly-Xaa-Xaa-Xaa-Gly-Xaa-Gly, and a nonsense region
Tyr-Xaa-Xaa-Xaa-Lys within the active site. What is important to
the activity is a catalytic tetrade consisting of
Tyr155-Lys159-Ser142-Asn114, which stabilize the steroid and the
ribose in the nicotinamide during the hydride transfer
(Alho-Richmond, S. et al., Mol. Cell. Endocrinol., 248: 208-213
(2006); Labrie, F. et al., Steroids, 62: 148-158 (1997); Nahoum, V.
et al., Faseb. J., 17: 1334-1336 (2003)).
[0030] The gene encoding 17.beta.-HSD1 is linked with the gene for
mammary and ovarian carcinomas that is very susceptible to
mutations and can be inherited, the BRCA1 gene, on chromosome
17q11-q21 (Labrie, F. et al., J. Mol. Endocrinol., 25: 1-16
(2000)). As has been demonstrated, the activity of 17.beta.-HSD1 is
higher in endometrial tissue and breast cancer cells as compared to
healthy tissue, which entails high intracellular estradiol levels,
which in turn cause proliferation and differentiation of the
diseased tissue (Bulun, S. E. et al., J. Steroid Biochem. Mol.
Biol., 79: 19-25 (2001); Miyoshi, Y. et al., Int. J. Cancer, 94:
685-689 (2001); Kitawaki, J., Journal of Steroid Biochemistry &
Molecular Biology, 83: 149-155 (2003); Pasqualini, J. R., Biochim.
Biophys. Acta., 1654: 123-143 (2004); Vihko, P. et al., Mol. Cell.
Endocrinol., 171: 71-76 (2001); Miettinen, M. et al., Breast Cancer
Res. Treat., 57: 175-182 (1999); Sasano, H. et al., J. Clin.
Endocrinol. Metab., 81: 4042-4046 (1996); Yoshimura, N. et al.,
Breast Cancer Res., 6: R46-55 (2004)). An inhibition of
17.beta.-HSD1 could result in the estradiol level being lowered and
thus lead to a regression of the estrogen-related diseases.
Further, selective inhibitors of 17.beta.-HSD1 could be used for
prevention when there is a genetic disposition for breast cancer
(Miettinen, M. et al., J. Mammary Gland. Biol. Neoplasia, 5:
259-270 (2000)).
[0031] Thus, this enzyme would suggest itself as a target for the
development of novel selective and non-steroidal inhibitors as
therapeutic agents in the battle against estrogen-related diseases.
However, there has not been a proof of concept to date.
[0032] In the literature, only a few compounds have been described
as inhibitors of 17.beta.-HSD1 (Poirier, D., Curr. Med. Chem., 10:
453-477 (2003)). Most inhibitors are steroidal compounds obtained
by different variations of the estrogen skeleton (Allan, G. M. et
al., 3. Med. Chem., 49: 1325-1345 (2006); Deluca, D. et al., Mol.
Cell. Endocrinol., 248: 218-224 (2006); WO2006/003012;
US2006/652461; WO2005/047303).
##STR00001##
[0033] Another class of compounds which has been described is the
so-called hybrid inhibitors (Qiu, W. et al., FASEB J., 16:
1829-1830 (2002); online: doi 10.1096/fj.02-0026fje), compounds
that, due to their molecular structure, not only attack at the
substrate binding site, but also undergo interactions with the
cofactor binding site. The inhibitors have the following structure:
[0034] adenosine moiety or simplified derivatives that can interact
with the cofactor binding site; [0035] estradiol or estrone moiety,
which interacts with the substrate binding site; and [0036] a
spacer of varying length as a linking element between the two
moieties.
##STR00002##
[0037] Among these compounds, inhibitors have been synthesized that
exhibit a good inhibition of the enzyme and a good selectivity for
17.beta.-HSD2 (compound B (Lawrence, H. R. et al., J. Med. Chem.,
48: 2759-2762 (2005))). In addition, the inventors consider that a
small estrogenic effect can be achieved by a substitution at the C2
of the steroid skeleton (Cushman, M. et al., J. Med. Chem., 38:
2041-2049 (1995); Leese, M. P. et al., J. Med. Chem., 48: 5243-5256
(2005)); however, this effect has not yet been demonstrated in
tests.
[0038] However, a drawback of these steroidal compounds may be a
low selectivity. With steroids, there is a risk that the compounds
will also attack other enzymes of the steroid biosynthesis, which
would lead to side effects. In addition, due to their steroidal
structure, they may have an affinity for steroid receptors and
function as agonists or antagonists.
[0039] Among the phytoestrogens, which have affinity for the
estrogen receptor and act as estrogens or anti-estrogens depending
on the physiological conditions, flavones, isoflavones and lignans
have been tested for an inhibitory activity (Makela, S. et al.,
Proc. Soc. Exp. Biol. Med., 217: 310-316 (1998); Makela, S. et al.,
Proc. Soc. Exp. Biol. Med., 208: 51-59 (1995); Brooks, J. D. et
al., J. Steroid Biochem. Mol. Biol., 94: 461-467 (2005)).
Coumestrol was found to be particularly potent, but of course
showed estrogenic activity (Nogowski, L., J. Nutr. Biochem., 10:
664-669 (1999)). Gossypol derivatives were also synthesized as
inhibitors (US2005/0228038). In this case, however, the cofactor
binding site rather than the substrate binding site is chosen as
the target site (Brown, W. M. et al., Chem. Biol. Interact.,
143-144, 481-491 (2003)), which might entail problems in
selectivity with respect to other enzymes utilizing NAD(H) or
NADP(H).
##STR00003##
[0040] In addition to diketones, such as 2,3-butanedione and
glyoxal, which were used for studies on the enzyme, suicide
inhibitors were also tested. However, these were found not to be
therapeutically utilizable since the oxidation rate of the alcohols
to the corresponding reactive form, namely the ketones, was too
weak (Poirier, D., Curr. Med. Chem., 10: 453-477 (2003)).
[0041] In other studies, Jarabak et al. (Jarabak, J. et al.,
Biochemistry, 8: 2203-2212 (1969)) examined various non-steroidal
inhibitors for their inhibitory effect, U-11-100A having been found
as the most potent compound in this group. However, as compared to
other non-steroidal compounds, U-11-100A is a weak inhibitor of
17.beta.-HSD1.
##STR00004##
[0042] As further non-steroidal inhibitors, thiophenepyrimidinones
have been examined (US2005/038053; Messinger, J. et al., Mol. Cell.
Endocrinol., 248: 192-198 (2006); WO2004/110459).
[0043] Azole derivatives with two or three hydroxyphenyl
substituents were presented as new estrogen receptor ligands (Fink,
B. E., et al., Chem. and Biol., 6: 205-219 (1999)). The
4-alkyl-1,3,5-triarylpyrrazoles published therein are potent
ligands while the bis(hydroxyphenyl)heterocycles have no
affinity.
[0044] The bissubstituted azoles 2,4-bis(4-methoxyphenyl)thiazole
and 4,4'-(1,3-thiazole-2,4-diyl)diphenol were already described by
Fink, B. E., et al., Chem. and Biol., 6: 205-219 (1999).
[0045] WO 00/19994 describes di- and triphenyl-substituted
five-membered heterocycles, wherein the phenyl radicals are
unsubstituted or carry parahydroxy groups, which have a high
affinity for the estrogen receptor.
[0046] Chandra, R., et al., Bioorg. & Med. Chem. Lett., 16:
1350-1352 (2006), describe 2,5-diphenyl-substituted thiophene
derivatives in which the phenyl radicals have para substituents and
which are suitable as .beta.-amyloid plaque detection reagents.
Demerseman, P., et al., 3. Chem. Soc., 23: 2720-2722 (1954),
describe the synthesis of 2,4-bis(4-hydroxyphenyl)- and
2,4-bis(4-methoxyphenyl)-thiophene.
[0047] Muller, G. et al., Bul. Soc. Chim. France, 533-535 (1949),
describe the synthesis of 2,5-diphenyl substituted pyrazines in
which the phenyl radicals are substituted with acetoxy or hydroxy
radicals in para and meta positions.
[0048] JP-A-03251494 employs mono- and dihydroxysubstituted
terphenyl compounds as developer compounds in thermal storage
materials, only one compound being mentioned that respectively has
a hydroxy group at one of the outer phenyl rings, namely
[1,1':3',1''-terphenyl]-4,4''-diol.
[0049] Guither, W. D., et al., Heterocycles, 12(6): 745-749 (1979),
describe the production of
3,6-bis(3-hydroxyphenyl)-s-tetrazine.
[0050] None of the compounds stated above was described as an
inhibitor of 178-HSD1.
SUMMARY OF THE INVENTION
[0051] Estradiol is the product of the reaction catalyzed by
17.beta.-HSD1. In addition, estradiol of all endogenous estrogens
is also the steroid hormone that shows the highest affinity for the
estrogen receptors (ER.alpha. and ER.beta.). Therefore, a great
homology between the binding sites of 17.beta.-HSD1, ER.alpha. and
ER.beta. is to be expected. In the therapeutical approach on which
the present invention is based, the inhibitors are supposed to
inhibit 17.beta.-HSD1 selectively without showing agonistic
activity on the estrogen receptors.
[0052] Proceeding from the available crystal structures of
17.beta.-HSD1, ER.alpha. and ER.beta., it was believed that there
are similarities in hydrophobic and hydrophilic regions. However,
significant differences can also be seen. In the binding site of
17.beta.-HSD1, there are polar amino acids (Tyr 218 and Ser 222),
for which there are no analogues in the estrogen receptors. In
contrast to 17.beta.-HSD1, the estrogen receptors have no cofactor
domain, so that more space is available in 17.beta.-HSD1 at
positions 15 and 16 of the steroid. The utilization of such
differences is of highest importance to the design of selective
17.beta.-HSD1 inhibitors. A wide variety of target compounds
including bis(methoxyphenyl) and bis(hydroxyphenyl) substituted
(hetero)aryl compounds have been synthesized, and their inhibitor
activity on 17.beta.-HSD1 and 17.beta.-HSD2 enzymes tested in vitro
in order to establish an active and selective leading structure. In
addition, studies relating to the ER affinity have been performed.
It has been found that certain diphenyl substituted (hetero)aryl
compounds, namely those compounds in which the phenyl radicals have
a meta substituent and a meta or para substituent relative to the
linkage with the central (hetero)aryl, are potent inhibitors of
17.beta.-HSD1. Thus, the invention relates to
(1) the use of compounds having the structure (I)
##STR00005##
wherein n is an integer selected from 0, 1 and 2;
A is C or N;
[0053] X is selected from CH, S, N, NH, --HC.dbd.N--, --N.dbd.CH--
and O; Y is selected from CH, --HC.dbd.CH--, S, N, O, NH and
C.dbd.S; Z is selected from CH, N, NH and O; R are independently
selected from halogen, hydroxy, --CN, --NO.sub.2, --N(R').sub.2,
--SR', alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl,
--SO.sub.3R', --NHSO.sub.2R', --R''--NHSO.sub.2R', --SO.sub.2NHR',
--R''--SO.sub.2NHR', --NHCOR', --CONHR', --R''--NHCOR',
--R''--CONHR', --COOR', --OOCR', --R''--COOR', --R''--OOCR',
--CHNR', --SO.sub.2R' and --SOR'; R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.5 independently have the meaning as stated for R
or are H; R' is selected from H, alkyl, aryl and heteroaryl; R'' is
selected from alkylene, arylene and heteroarylene; wherein said
alkyl, alkylene, aryl, arylene, heteroaryl and heteroarylene
radicals in R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R' and
R'' may be substituted with 1 to 5 radicals R''' and wherein the
radicals R''' are independently selected from halogen, hydroxy,
--CN, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, --SH,
alkylsulfanyl, arylsulfanyl, aryl, heteroaryl, --COON, --COOalkyl,
--CH.sub.2OH, --NO.sub.2 and --NH.sub.2; and pharmacologically
acceptable salts thereof, for the preparation of a medicament for
the treatment and prophylaxis of hormone-related diseases; (2) a
compound of structure (I)
##STR00006##
wherein n, A, X, Y, Z, R, R.sub.I, R.sub.2, R.sub.3, R.sub.4 and
R.sub.5 have the meanings as stated above in (1), with the proviso
that if n is 1, A is C, X is N, Y is S and Z is CH, R.sub.1,
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are H, then the radicals R
are not both in para position relative to the linkage of the
central (hetero)aryl group and are not at the same time OH or
methoxy; and pharmacologically acceptable salts thereof; (3) a
medicament or pharmaceutical composition containing at least one of
the compounds as defined in (2) and optionally a pharmacologically
suitable carrier; (4) a process for the preparation of the
compounds as defined in (2), comprising a reaction according to the
following reaction scheme:
##STR00007##
wherein the variables have the meanings as stated above in (2); and
(5) a process for the treatment and prophylaxis of hormone-related
diseases in a human or animal, comprising administering a compound
having a structure (I) as defined above in (1) or (2).
[0054] In particular, the two phenyl radicals having a polar group,
preferably in p- or m-position relative to the central (hetero)aryl
radical (such as hydroxyphenyl radicals), seem to be important to
the design of the compounds of the present invention as active
substances, since they mimic the hydroxy groups on positions 3 and
1.7 of estradiol and obviously serve as hydrophilic anchor sites in
the 17.beta.-HSD1 binding site. One of the phenyl radicals has to
carry the polar group in m-position, while the other may carry it
in m- or p-position in order to have 178-HSD1 inhibitor activity
(the p-/p-substituted compounds have been shown to be no
17.beta.-HSD1 inhibitors). The positions of the hetero atoms within
the (hetero)aryl ring linking the two phenyl radicals was varied in
order to examine their role in the inhibition of the enzyme. Also,
the positions of the polar groups of the phenyl radicals were
changed in order to find their optimum arrangement.
DETAILED DESCRIPTION OF THE INVENTION
[0055] In the compounds of formula (I) of the invention, the
variables and the terms used for their characterization have the
following meanings:
[0056] "Alkyl radicals", "haloalkyl radicals", "alkoxy radicals"
and "haloalkoxy radicals" within the meaning of the invention may
be straight-chain, branched-chain or cyclic, and saturated or
(partially) unsaturated. Preferable alkyl radicals and alkoxy
radicals are saturated or have one or more double and/or triple
bonds. Of straight-chain or branched-chain alkyl radicals,
preferred are those having from 1 to 10 carbon atoms, more
preferably those having from 1 to 6 carbon atoms, even more
preferably those having from 1 to 3 carbon atoms. Of the cyclic
alkyl radicals, more preferred are mono- or bicyclic alkyl radicals
having from 3 to 15 carbon atoms, especially monocyclic alkyl
radicals having from 3 to 8 carbon atoms.
[0057] "Lower alkyl radicals", "halogenated lower alkyl radicals",
"lower alkoxy radicals" and "halogenated lower alkoxy radicals"
within the meaning of the invention are straight-chain,
branched-chain or cyclic saturated lower alkyl radicals and lower
alkoxy radicals or those having a double or triple bond. Of the
straight-chain ones, those having from 1 to 6 carbon atoms,
especially 1 to 3 carbon atoms, are particularly preferred. Of the
cyclic ones, those having from 3 to 8 carbon atoms are particularly
preferred.
[0058] "Aryls" in the definition of R, R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.5 include mono-, bi- and tricyclic aryl radicals
having from 3 to 18 ring atoms, which may optionally be anellated
with one or more saturated rings. Particularly preferred are
anthracenyl, dihydronaphthyl, fluorenyl, hydrindanyl, indanyl,
indenyl, naphthyl, naphthenyl, phenanthrenyl, phenyl and
tetralinyl.
[0059] Unless stated otherwise, "heteroaryl radicals" in the
definition of R, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are
mono- or bicyclic heteroaryl radicals having from 3 to 12 ring
atoms and preferably having from 1 to 5 heteroatoms selected from
nitrogen, oxygen and sulfur, which may be anellated with one or
more saturated rings. The preferred nitrogen-containing monocyclic
and bicyclic heteroaryls include benzimidazolyl, benzothiazolyl,
benzoxazolyl, quinazolinyl, quinolyl, quinoxalinyl, cinnolinyl,
dihydroindolyl, dihydroisoindolyl, dihydropyranyl, dithiazolyl,
homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl,
indazolyl, indolyl, isoquinolyl, isoindolyl, isothiazolidinyl,
isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl,
oxazolidinyl, oxazolyl, phthalazinyl, piperazinyl, piperidyl,
pteridinyl, purinyl, pyrazolidinyl, pyrazinyl, pyrazolyl,
pyrazolinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolidinyl,
pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, tetrazinyl, tetrazolyl,
tetrahydropyrrolyl, thiadiazolyl, thiazinyl, thiazolidinyl,
thiazolyl, triazinyl and triazolyl. Particularly preferred are
mono- or bicyclic heteroaryl radicals with 5 to 10 ring atoms,
preferably having from 1 to 3 nitrogen atoms, oxazolyl, imidazolyl,
pyridyl and pyrimidyl being more preferred.
[0060] "Alkylenes", "lower alkylenes", "arylenes" and
"heteroarylenes" within the meaning of this invention include the
bivalent equivalents of the above defined alkyl, lower alkyl, aryl
and heteroaryl radicals.
[0061] "Halogen" includes fluorine, chlorine, bromine and
iodine.
[0062] "Pharmaceutically acceptable salts" within the meaning of
the present invention include salts of the compounds with organic
acids (such as lactic acid, acetic acid, amino acid, oxalic acid
etc.), inorganic acids (such as HCl, HBr, phosphoric acid etc.),
and, if the compounds have acid substituents, also with organic or
inorganic bases. Preferred are salts with HCl.
[0063] The compounds according to embodiments (1) and (2) of the
invention preferably have the following (hetero)aryl radicals as
the central ring:
n is 1, A is N, X is CH, Y is C.dbd.S and Z is NH (i.e., the
central ring is a 1,4-disubstituted 1,3-dihydroimidazole-2-thione);
n is 1, A is N, X is CH, Y is CH and Z is N (a 1,4-disubstituted
1H-imidazole); n is 1, A is C, X is O or NH, Y is CH and Z is N (a
2,5-disubstituted oxazole or 1H-imidazole); n is 1, A is C, X is N,
Y is O and Z is CH (a 2,4-disubstituted oxazole); n is 1, A is C, X
is CH, Y is O and Z is N (a 3,5-disubstituted isoxazole); n is 1, A
is C, X is S, Y is N or CH and Z is CH (a 2,5-disubstituted
thiazole or thiophene); n is 1, A is C, X is N or CH, Y is S and Z
is CH (a 2,4-disubstituted thiazole or thiophene); n is 0, A is C,
Y is S and Z is --HC.dbd.CH-- (a 2,3-disubstituted thiophene); n is
1, A is C, X is CH, Y and Z are N and NH (a 3,5-disubstituted
1H-pyrazole); n is 1, A is C, X is S or O, Y and Z are N (i.e., a
2,5-disubstituted 1,3,4-thiadiazole or 1,3,4-oxadiazole); n is 1, A
is C, X and Z are N and Y is S (a 3,5-disubstituted
1,2,4-thiadiazole); n is 2, A is C, X is CH, Y and Z are CH (a
1,4-disubstituted benzene); n is 1, A is C, X and Y are CH and Z is
--HC.dbd.CH-- (a 1,3-disubstituted benzene); n is 1, A is C, X is
--N.dbd.CH--, Y is CH and Z is CH or N (a 2,5-disubstituted
pyridine or pyrazine); and n is 2, and X, Y and Z are N (i.e., a
3,6-disubstituted 1,2,4,5-tetrazine).
[0064] Of the above mentioned central rings, the thiophene,
thiazole, thiadiazole, benzene, pyridine or tetrazine rings are
particularly preferred.
[0065] It is preferred within the meaning of the present invention
if the radicals R are independently selected from halogen, hydroxy,
--CN, --NO.sub.2, --SH, --NHR', --SO.sub.3R', alkyl, haloalkyl,
alkoxy, haloalkoxy, alkylsulfanyl, aryl, heteroaryl, arylsulfanyl,
--NHSO.sub.2R', --R''--NHSO.sub.2R', --SO.sub.2NHR',
--R''--SO.sub.2NHR', --NHCOR', --CONHR', --R''--NHCOR',
--R''--CONHR', --COOR', --OOCR', --R''--COOR', --R''--OOCR',
--CHNR', --SO.sub.2R' and --SOR', wherein R' is H, lower alkyl or
phenyl and R'' is lower alkylene or phenylene. Of these, preferred
radicals R include halogen, hydroxy, --CN, --NO.sub.2, --SH,
--NHR', --SO.sub.3R', lower alkyl, halogenated lower alkyl, lower
alkoxy, halogenated lower alkoxy, (lower alkyl)sulfanyl, aryl,
heteroaryl, arylsulfanyl, --NHSO.sub.2R', --SO.sub.2NHR', NHCOR',
--CONHR', --COOR', --OOCR', --SO.sub.2R' and --SOR' (wherein R' is
H, lower alkyl or phenyl), and it is particularly preferred if R
are independently selected from halogen, hydroxy, --CN, --NO.sub.2,
--SH, --NH.sub.2, SO.sub.3R', lower alkyl, halogenated lower alkyl,
lower alkoxy, (lower alkyl)sulfanyl, arylsulfanyl, --NHSO.sub.2R',
--SO.sub.2NHR', --NHCOR', --CONHR', --COOR', --OOCR', --SO.sub.2R'
and --SOR', wherein R' is H, lower alkyl or phenyl.
[0066] Within the meaning of the invention, it is preferred that
the radicals R are in meta- or para-position, namely one of R is in
meta-position, and the other is in meta- or para-position relative
to the linkage to the central (hetero)aryl group.
[0067] Also preferred within the meaning of the present invention
if the radicals R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are
independently selected from H, halogen, hydroxy, --CN, lower alkyl,
halogenated lower alkyl, lower alkoxy, (lower alkyl)sulfanyl, aryl,
heteroaryl, arylsulfanyl, --NHSO.sub.2R', --SO.sub.2NHR', --NHCOR',
--CONHR', --COOR', --SO.sub.2R' and --SOR', wherein R' is H, lower
alkyl or phenyl. Preferably among the mentioned radicals, they are
independently selected from H, halogen, hydroxy, --CN, lower alkyl,
halogenated lower alkyl, lower alkoxy, halogenated lower alkoxy,
(lower alkyl)sulfanyl, --NHSO.sub.2R', --SO.sub.2NHR', --NHCOR',
--CONHR', --COOR', --OOCR', --SO.sub.2R' and --SOR', wherein R' is
H or lower alkyl.
[0068] Particularly preferred are those compounds in which the
radicals R are independently selected from halogen, hydroxy, --CN,
--COON, --NO.sub.2, --NH.sub.2, --SH, --SO.sub.3H,
SO.sub.2NH.sub.2, --NHSO.sub.2-- (lower alkyl), lower alkyl,
halogenated lower alkyl, lower alkoxy and halogenated lower alkoxy,
more preferably independently selected from hydroxy, --COON,
--NHSO.sub.2CH.sub.3, --SH, --CN and C.sub.1-3-alkoxy, and are in
meta- or para-position, namely one in meta-position and the other
in meta- or para-position (relative to the linkage to the central
(hetero)aryl group). Particularly preferred are those compounds in
which the radicals R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5
are independently selected from H, halogen, halogenated lower alkyl
and lower alkyl, more preferably independently selected from H, F,
CF.sub.3 and CH.sub.3.
[0069] Compounds of structure (I) to be particularly mentioned
include
4-(3-hydroxyphenyl)-1-(4-hydroxyphenyl)-1,3-dihydroimidazole-2-thione
(1);
4-(4-hydroxyphenyl)-1-(3-hydroxyphenyl)-1,3-dihydroimidazole-2-thion-
e (2); 1,4-bis-(4-hydroxyphenyl)-1,3-dihydroimidazole-2-thione (3);
3-[1-(4-hydroxyphenyl)-1H-imidazole-4-yl]phenol (4);
3-[4-(4-hydroxyphenyl)-1H-imidazole-4-yl]phenol (5);
4,4'-bis-(1H-imidazole-1,4-diyl)diphenol (6);
4,4'-(1,3-oxazole-2,5-diyl)diphenol (7);
3-[5-(4-hydroxyphenyl)-1,3-oxazole-2-yl]phenol (8);
3-[4-(4-hydroxyphenyl)-1,3-oxazole-2-yl]phenol (9);
3-[2-(4-hydroxyphenyl)-1H-imidazole-5-yl]phenol (10);
3-[5-(4-hydroxyphenyl)-1H-imidazole-2-yl]phenol (11);
4,4'-(1H-imidazole-2,5-diyl)diphenol (12);
4,4'-(1H-pyrazole-3,5-diyl)diphenol (13);
3-[3-(4-hydroxyphenyl)-1H-pyrazole-5-yl]phenol (14);
3-[5-(4-hydroxyphenyl)-1H-pyrazole-3-yl]phenol (15);
4,4'-isoxazole-3,5-diyldiphenol (16);
3-[5-(4-hydroxyphenyl)isoxazole-3-yl]phenol (17);
3-[3-(4-hydroxyphenyl)isoxazole-5-yl]phenol (18);
3-[5-(4-hydroxyphenyl)-1,3-thiazole-2-yl]phenol (19);
3-[2-(4-hydroxyphenyl)-1,3-thiazole-5-yl]phenol (20);
4,4'-(1,3-thiazole-2,5-diyl)diphenol (21);
3,3'-(1,3-thiazole-2,5-diyl)diphenol (22);
3-[4-(4-hydroxyphenyl)-1,3-thiazole-2-yl]phenol (23);
3-[2-(4-hydroxyphenyl)-1,3-thiazole-4-yl]phenol (24);
4,4'-(1,3-thiazole-2,4-diyl)diphenol (25; not covered by embodiment
(2)); 3,3'-(1,3-thiazole-2,4-diyl)diphenol (26);
4,4'-thiene-2,3-diyldiphenol (27);
3-[3-(4-hydroxyphenyl)-2-thienyl]phenol (28);
3-[5-(4-hydroxyphenyl)-2-thienyl]phenol (29);
4,4'-thiene-2,5-diyldiphenol (30); 3,3'-thiene-2,5-diyldiphenol
(31); 3-[5-(4-hydroxyphenyl)-3-thienyl]phenol (32);
3-[4-(4-hydroxyphenyl)-2-thienyl]phenol (33);
3,3'-thiene-2,4-diyldiphenol (34);
3,3'-(1,3,4-oxadiazole-2,5-diyl)diphenol (35);
3,3'-(1,3,4-thiadiazole-2,5-diyl)diphenol (36);
3,3'-(1,2,4-thiadiazole-2,5-diyl)diphenol (37);
3-[3-(4-methoxyphenyl)-1,2,4-thiadiazole-5-yl]phenol (38);
4,4'-(1,2,4-thiadiazole-3,5-diyl)diphenol (39);
3-[3-(4-hydroxyphenyl)-1,2,4-thiadiazole-5-yl]phenol (40);
[1,1',3',1'']terphenyl-4,4''-diol (41);
[1,1',4',1'']terphenyl-3,3'-diol (42);
[1,1',3',1'']terphenyl-4,3''-diol (43);
[1,1',4',1'']terphenyl-4,3''-diol (44);
4-[5-(3-hydroxyphenyl)-2-thienyl]-2-methylphenol (45);
4-[5-(3-hydroxyphenyl)-2-thienyl]benzene-1,2-diol (46);
2-fluoro-4-[5-(3-hydroxyphenyl)-2-thienyl]phenol (47);
2,6-difluoro-4-[5-(3-hydroxyphenyl)-2-thienyl]phenol (48);
4-[5-(3-hydroxyphenyl)-2-thienyl]-2-(trifluoromethyl)phenol (49);
3-[5-(3-fluorophenyl)-2-thienyl]phenol (50);
N-{3-[5-(3-hydroxyphenyl)-2-thienyl]phenyl}methanesulfonamide (51);
3-(5-phenyl-2-thienyl)phenol (52);
3-[5-(4-hydroxyphenyl)-2-thienyl]-5-methylphenol (53);
3-[5-(4-fluorophenyl)-2-thienyl]phenol (54);
4-[5-(3-hydroxyphenyl)-3-thienyl]-2-methylphenol (55);
4-[2-(3-hydroxyphenyl)-1,3-thiazot-5-yl]-2-methylphenol (56);
3,3'-pyridine-2,5-diyldiphenol (57) and
3,3'-(1,2,4,5-tetrazine-3,6-diyl)diphenol (59), wherein compounds
(19), (20), (22), (24), (26), (29), (31), (32), (33), (36), (37),
(42), (45), (46), (47), (48), (49), (55), (56), (57) and (59) are
particularly preferred.
[0070] In preferred embodiments of (1), (3) and (5), the above
mentioned compounds of structure (I) are used for the treatment and
prophylaxis of estrogen-related diseases, especially endometriosis,
endometrial carcinoma, adenomyosis and breast cancer, and for the
treatment of androgen-related diseases, especially prostate
carcinoma and benign prostate hyperplasia (BPH).
[0071] The compounds of the present invention can be administered
in any dosage form known to the skilled person, oral administration
being the preferred route of administration, however.
[0072] The process for the preparation according to embodiment (4)
of the invention preferably comprises a so-called Suzuki coupling.
The 2,5-disubstituted thiophenes according to the present invention
can be prepared according to the following synthetic route:
##STR00008## [0073] R.sub.1.dbd.R.sub.2=H: compound (29) [0074]
R.sub.1=H, R.sub.2=CH.sub.3: compound (45) [0075] R.sub.1=H,
R.sub.2=OH: compound (46) [0076] R.sub.1=H, R.sub.2=F: compound
(47)= [0077] R.sub.1=H, R.sub.2=CF.sub.3, compound (49) [0078]
R.sub.1=F, R.sub.2=F: compound (48)
[0079] The quantity of active substance administered, i.e., the
dose employed, depends on the kind and severity of the disease to
be treated, the dosage form and therapy form, the age and
constitution of the patient, and is individually adapted to the
concrete situation by the attending physician within the scope of
their general technical skill.
[0080] The invention is now further illustrated by means of the
following Examples, which do not however limit the invention.
EXAMPLES
Materials and Analytical Methods
[0081] IR spectra of powders were recorded with a Bruker "Vektor
33" FT infrared spectrometer. .sup.1H NMR and .sup.13C NMR spectra
were recorded with Bruker AW-500 (500 MHz) equipment. The chemical
shifts are stated in parts per million (ppm), TMS was the internal
standard for recordings in CDCl.sub.3, CD.sub.3OD,
CD.sub.3COCD.sub.3 and DMSO-d.sub.6. All coupling constants (3) are
stated in Hz. The mass spectra were measured with a TSQ Quantum.
The reagents and solvents were obtained from commercial sources and
used without any further purification. Column chromatographies were
performed over silica gel (63-70 .mu.m), the course of the reaction
was monitored by means of thin-layer chromatography over Alugram
SilG/UV.sub.254 plates (Macherey-Nagel, Duren, Germany). The
preparative TLC glass plates (SilG100/UV.sub.254) were purchased
from the company Macherey-Nagel. The layer thickness was 1 mm. The
reactions requiring a microwave source were performed in a CEM
"Discover DU5200".
General Synthetic Protocols:
[0082] Method A (Suzuki): One equivalent of aryl bromide, 1.2
equivalents of boric acid, 2 equivalents of a 10% sodium carbonate
solution and 0.02 equivalent of
palladiumtetrakis(triphenylphosphine) were dissolved Under nitrogen
in 10 ml of oxygen-free toluene and heated under reflux for 18
hours. After cooling to room temperature, 20 ml of water is added.
After extraction of the organic phase, the aqueous phase is washed
with ethyl acetate, the combined organic phases are washed with a
saturated sodium chloride solution, dried over magnesium sulfate,
and the solvent is finally removed on a rotary evaporator. The raw
product obtained is purified by column chromatography.
[0083] Method B (Suzuki): One equivalent of aryl bromide, 1.2
equivalents of boric acid, 2 equivalents of a 10% cesium carbonate
solution and 0.02 equivalent of
palladiumtetrakis(triphenylphosphine) were dissolved under nitrogen
in 10 ml of oxygen-free toluene and heated under reflux for 18
hours. After cooling to room temperature, 20 ml of water is added.
After extraction of the organic phase, the aqueous phase is washed
with ethyl acetate, the combined organic phases are washed with a
saturated sodium chloride solution, dried over magnesium sulfate,
and the solvent is finally removed, on a rotary evaporator. The raw
product obtained is purified by column chromatography.
[0084] Method C (Suzuki): One equivalent of aryl bromide, 1.2
equivalents of boric acid, 2 equivalents of a 10% cesium carbonate
solution and 0.02 equivalent of
palladiumtetrakis(triphenylphosphine) were dissolved under nitrogen
in 10 ml of oxygen-free tetrahydrofuran and heated to reflux under
nitrogen for 20 hours. After cooling to room temperature, 20 ml of
water is added. After extraction of the organic phase, the aqueous
phase is washed with ethyl acetate, the combined organic phases are
washed with a saturated sodium chloride solution, dried over
magnesium sulfate, and the solvent is finally removed on a rotary
evaporator. The raw product obtained is purified by column
chromatography.
[0085] Method D (ether cleavage): One equivalent of the dimethoxy
derivative is dissolved in 10 ml of anhydrous dichloromethane. 75
equivalents of boron trifluoride/dimethyl sulfide complex is added
dropwise to the reaction mixture and stirred at room temperature
for 20 hours. 15 ml of Water is added to the reaction mixture, and
the phases are separated. The aqueous phase is washed with 15 ml of
ethyl acetate, and the combined organic phases are washed with a
saturated sodium chloride solution, dried over magnesium sulfate,
the solvent is removed on a rotary evaporator, and the residue is
purified by preparative thin-layer chromatography.
[0086] Method E (ether cleavage): One equivalent of the dimethoxy
derivative is dissolved in 10 ml of anhydrous dichloromethane and
cooled down to -78.degree. C. 6 equivalents of a 1 M boron
tribromide solution is added dropwise to the reaction mixture and
stirred for 20 hours. 15 ml of water is added to the reaction
mixture, and the phases are separated. The aqueous phase is washed
with 15 ml of ethyl acetate, and the combined organic phases are
washed with a saturated sodium chloride solution, dried over sodium
sulfate, the solvent is removed on a rotary evaporator, and the
residue is purified by preparative thin-layer chromatography.
Example 1
Chemical and Physical Characterization of the Synthesized
Compounds
1. 1-(3-Methoxyphenyl)-2-[(4-methoxyphenyl)amino]ethanone
##STR00009##
[0088] Synthesis: In cooled DMF, 1.87 mmol of p-anisidine, 1.87
mmol of 3-methoxyphenacylbromide and 1.87 mmol of triethylamine are
stirred for 7 hours and then poured on ice. The precipitate
obtained is filtered, dried and purified by column chromatography
(hexane/ethyl acetate 6:4); yield: 70%, yellow powder, Rf:
(hexane/ethyl acetate 5:5) 0.79; .sup.1H NMR (CDCl.sub.3, 500 MHz):
7.55-7.57 (dt, J=1.50 Hz and J=7.80 Hz, 1H, Harom), 7.51 (m, 1H,
Harom), 7.38 (t, J=7.80 Hz, 1H), 7.12-7.14 (ddd, J=0.60 Hz, J=2.50
Hz and J=8.80 Hz, 1H, Harom), 6.80 (dd, J=2.20 Hz and J=8.80 Hz,
2H, Harom), 6.66 (dd J=2.20 Hz and J=8.80 Hz, 2H, Harom), 4.54 (s,
2H), 3.85 (s, 3H, OMe), 3.73 (s, 3H, OMe); .sup.13C NMR
(CDCl.sub.3, 125 MHz): 195.40, 160.00, 152.45, 141.45, 136.35,
129.85, 120.15, 120.10, 115.00, 114.35, 112.25, 55.80, 55.50,
51.45; IR: 3383, 2693, 1686, 1511, 1232, 784 cm.sup.-1.
2. 1-(4-Methoxyphenyl)-2-(3-methoxyphenylamino)ethanone
##STR00010##
[0090] Synthesis: In cooled DMF, 1.87 mmol of m-anisidine, 4.40
mmol of 3-methoxyphenacylbromide and 4.40 mmol of triethylamine are
stirred for 2 hours and then poured on ice. The precipitate
obtained is filtered, dried and purified by column chromatography
(hexane/ethyl acetate 6:4); yield: 70%, yellow powder. Rf:
(hexane/ethyl acetate 5:5): 0.76; .sup.1H NMR (CDCl.sub.3, 500
MHz): 7.97 (m, 2H, Harom), 7.12 (t, J=8.20 Hz, 1H, Harom), 6.96 (m,
2H, Harom), 6.30 (m, 2H, Harom), 6.29 (t, J=2.20 Hz, 1H, Harom),
4.54 (s, 2H), 3.87 (s, 3H, OMe), 3.78 (s, 3H, OMe); .sup.13C NMR
(CDCl.sub.3, 125 MHz): 192.15, 163.10, 159.90, 147.15, 129.15,
129.05, 113.05 (2C), 105.50, 102.30, 98.50, 54.55, 49.15; IR: 3403,
1681, 1210, 827 cm.sup.-1.
3. 1-(4-Methoxyphenyl)-2-(4-methoxyphenylamino)ethanone
##STR00011##
[0092] Synthesis: In cooled DMF, 8.10 mmol of p-anisidine, 8.10
mmol of 4-methoxyphenacylbromide and 8.10 mmol of triethylamine are
stirred for 2 hours and then poured on ice. The precipitate
obtained is filtered, dried and purified by column chromatography
(hexane/ethyl acetate 6:4); yield: 98%, yellow powder. Rf
(hexane/ethyl acetate 5:5): 0.78; .sup.1H NMR (CDCl.sub.3, 500
MHz): 7.98 (d, J=9.10 Hz, 2H, Harom), 6.95 (d, J=9.10 Hz, 2H,
Harom), 6.80 (m, 2H, Harom), 6.73 (m, 2H, Harom), 4.53 (s, 2H),
3.87 (s, 3H, OMe), 3.74 (s, 3H, OMe). .sup.13C NMR (CDCl.sub.3, 125
MHz): 193.65, 164.05, 152.80, 140.95, 130.10, 127.95, 115.05,
114.95, 114.05, 55.80, 51.35; IR: 3065, 1512, 1251, 750
cm.sup.-1.
4.
4-(3-Methoxyphenyl)-1-(4-methoxyphenyl)-1,3-dihydroimidazole-2-thione
##STR00012##
[0094] Synthesis: 6.11 mmol of
1-(3-methoxyphenyl)-2-(4-methoxyphenylamino)ethanone is dissolved
in 20 ml of methanol and heated to boiling for 5 min. 6.11 mmol of
potassium thiocyanate and 60 .mu.l of concentrated hydrochloric
acid are added, and the mixture is heated to boiling for 18 h.
After cooling to room temperature, 50 ml of water is added. The
precipitate obtained is subjected to suction filtration, dried and
purified by column chromatography (hexane/ethyl acetate. 9:1);
yield: 28%, white-yellow powder. Rf (ethyl acetate): 0.71; .sup.1H
NMR (CDCl.sub.3, 500 MHz): 7.36 (d, J=9.40 Hz, 2H, Harom) 7.26-7.30
(m, 2H, Harom), 7.10 (d, J=7.80 Hz, 2H, Harom), 6.84 (m, 1H,
Harom), 6.81 (d, J=8.80 Hz, 2H, Harom), 3.82 (s, 3H, OMe), 3.72 (s,
3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz): 175.45, 160.05,
159.65, 129.70, 127.55, 117.45, 114.15 (2C), 113.95, 110.00, 55.45,
55.40, IR: 1626, 1514, 1222, 1037, 824 cm.sup.-1; MS (APCI):
313:(M+H).sup.+.
5.
4-(4-Methoxyphenyl)-1-(3-methoxyphenyl)-1,3-dihydroimidazole-2-thione
##STR00013##
[0096] Synthesis: 2.90 mmol of
1-(4-methoxyphenyl)-2-(3-methoxyphenylamino)ethanone is dissolved
in 20 ml of methanol and heated to boiling for 5 min. 2.90 mmol of
potassium thiocyanate and 60 .mu.l of concentrated hydrochloric
acid are added, and the mixture is heated to boiling for 18 hours.
After cooling to room temperature, 50 ml of water is added. The
precipitate obtained is subjected to suction filtration, dried and
purified by column chromatography (hexane/ethyl acetate 9:1).
Yield: 16%, white powder, Rf (D/M 4%): 0.60. .sup.1H NMR
(CDCl.sub.3, 500 MHz): 7.51 (d, J=8.50 Hz, 2H), 7.38 (t, J=7.80 Hz,
1H), 7.27 (s, 1H), 7.18 (d, J=7.80 Hz, 1H, Harom), 6.97 (dd, J=2.50
Hz and J=8.50 Hz, 1H, Harom), 6.89 (d, J=8.50 Hz, 2H, Harom), 3.84
(s, 3H, OMe), 3.79 (s, 3H, OMe). .sup.13C NMR (CDCl.sub.3, 125
MHz): 188.00, 160.00, 129.95, 126.50, 118.00, 114.65 (2C), 111.80,
55.60, 55.35; IR: 3055, 1601, 1455, 1181, 825 cm.sup.-1; MS (ESI):
313 (M+H).sup.+.
6. 1,4-Bis-(4-methoxyphenyl)-1,3-dihydroimidazole-2-thione
##STR00014##
[0098] Synthesis: 7.40 mmol of
1-(4-methoxyphenyl)-2-(4-methoxyphenylamino)-ethanone is dissolved
in 20 ml of methanol and heated to boiling for 5 min. 7.40 mmol of
potassium thiocyanate and 60 .mu.l of concentrated hydrochloric
acid are added, and the mixture is heated to boiling for 5 h. After
cooling to room temperature, 50 ml of water is added. The
precipitate obtained is subjected to suction filtration, dried and
purified by column chromatography (hexane/ethyl acetate 9:1).
Yield: 79%, white-yellow powder; Rf (ethyl acetate): 0.77; .sup.1H
NMR (CDCl.sub.3+2 drops of CD.sub.3OD, 500 MHz): 7.42 (dd, J=8.80
Hz and)=1.80 Hz, 2H, Harom), 7.39 (dd, J=8.80 Hz and J=1.80 Hz,
2H), 6.92 (m, 3H, Harom), 6.87 (dd, J=8.80 Hz and J=1.80 Hz, 2H,
Harom), 3.77 (s, 3H, OMe), 3.76 (s, 3H, OMe); .sup.13C NMR
(CDCl.sub.3+2 drops of CD.sub.3OD, 125 MHz): 157.50, 157.15,
156.75, 124.95 (2C), 123.65 (2C), 112.20 (2C), 111.95 (2C), 53.15,
52.95; IR: 3373, 2958, 1673, 1512, 1237, 816 cm.sup.-1. MS (APCI):
313:(M+H)..sup.+.
7.
4-(3-Hydroxyphenyl)-1-(4-hydroxyphenyl)-1,3-dihydroimidazole-2-thione
(1)
##STR00015##
[0100] Synthesis: Prepared from 0.32 mmol of
4-(3-methoxyphenyl)-1-(4-methoxyphenyl)-1,3-dihydroimidazole-2-thione
according to method D. Purification: preparative thin-layer
chromatography (ethyl acetate). Yield: 61%, orange powder; Rf
(ethyl acetate): 0.61; .sup.1H NMR (CD.sub.3SOCD.sub.3, 500 MHz):
12.76 (s, 1H, SH), 7.64 (s, 1H, Harom), 7.39 (d, J=8.50 Hz, 2H,
Harom), 7.15-7.19 (m, 2H, Harom), 7.09 (s, 1H, Harom), 6.84 (d,
J=8.50 Hz, 2H, Harom), 6.69-6.71 (m.1H, Harom). .sup.13C NMR
(CD.sub.3SOCD.sub.3, 125 MHz): 162.30, 157.60, 156.85, 129.90,
129.20, 128.95, 127.15, 116.15, 115.10 (2C), 114.85, 111.10; IR:
3214, 1604, 1514, 1395, 1101, 833, 750 cm.sup.-1; MS (APCI):
283:M..sup.+.
8.
4-(4-Hydroxyphenyl)-1-(3-hydroxyphenyl)-1,3-dihydroimidazole-2-thione
(2)
##STR00016##
[0102] Synthesis: Prepared from 0.32 mmol of
4-(3-methoxyphenyl)-1-(4-methoxyphenyl)-1,3-dihydroimidazole-2-thione
according to method D. Purification: preparative thin-layer
chromatography (ethyl acetate). Yield: 37%, yellow powder; Rf (E
pure): 0.59; .sup.1H NMR (CD.sub.3SOCD.sub.3, 500 MHz): 12.75 (s,
1H, SH), 7.62 (s, 1H, Harom), 7.40 (d, J=8.50 Hz, 2H, Harom),
7.13-7.18 (m, 2H, Harom), 7.07 (s, 1H, Harom), 6.83 (d, J=8.50 Hz,
2H, Harom), 6.66-6.79 (m.1H, Harom). .sup.13C NMR
(CD.sub.3SOCD.sub.3, 125 MHz): 162.35, 157.65, 156.95, 129.85,
129.00, 128.90, 127.20, 116.20 (2C), 115.05, 114.90, 111.25; IR:
3213, 1600, 1514, 1392, 1100, 845, 750 cm.sup.-1; MS (APCI):
283:M..sup.+.
9. 1,4-Bis(4-hydroxyphenyl)-1,3-dihydroimidazole-2-thione (3)
##STR00017##
[0104] Synthesis: Prepared from 0.32 mmol of
4-(3-methoxyphenyl)-1-(4-methoxyphenyl)-1,3-dihydroimidazole-2-thione
according to method D. Purification: preparative thin-layer
chromatography (ethyl acetate). Yield: 36%. Rf (ethyl acetate):
0.60; .sup.1H NMR (CD.sub.3OD, 500 MHz): 7.49 (d, J=8.80 Hz, 2H,
Harom) 7.42 (d, J=8.80 Hz, 2H, Harom), 7.34 (s, 1H, Harom), 6.92
(d, J=8.80 Hz, 2H, Harom), 6.87 (d, J=8.80 Hz, 2H, Harom);
[0105] .sup.13C NMR (CD.sub.3OD, 125 MHz): 162.00, 159.05, 158.80,
131.20, 131.10, 131.00, 128.55, 127.30, 120.55, 116.90, 116.50,
115.95; IR: 3135, 2469, 2072, 1511, 1116, 973, 836 cm.sup.-1; MS
(APCI): 285: (M)..sup.+, 286: (M+H).sup.+.
10. 4-(3-Methoxyphenyl)-1-(4-methoxyphenyl)-1H-Imidazole
##STR00018##
[0107] Synthesis: 0.48 mmol of
4-(3-methoxyphenyl)-1-(4-methoxyphenyl)-1,3-dihydroimidazole-2-thione
is dissolved in 5 ml of cooled glacial acetic acid. 0.16 mmol of
sodium nitrite is dissolved in a 33% aqueous nitric acid solution
and slowly added dropwise to the reaction mixture over 20 minutes.
The reaction is quenched with ammonium hydroxide. The precipitate
obtained is filtered off, dried and purified by column
chromatography (ethyl acetate/methanol 2%); yield: 52%, white
powder; Rf: (ethyl acetate): 0.44; .sup.1H NMR (CDCl.sub.3, 500
MHz): 8.90 (s, 1H, Harom) 7.62 (s, 1H, Harom), 7.56 (s, 1H, Harom),
7.46 (m, 3H, Harom), 7.35 (t, J=7.80 Hz, 1H, Harom), 7.09 (d,
J=8.50 Hz, 2H, Harom), 6.97 (dd, J=1.80 Hz and J=8.20 Hz, 1H,
Harom), 3.94 (s, 3H, OMe), 3.88 (s, 3H, OMe); .sup.13C NMR
(CDCl.sub.3, 125 MHz): 161.10, 160.45, 136.10, 133.00, 130.50,
127.00, 123.80, 118.00, 117.10, 115.75, 111.00, 56.05, 55.80; IR:
2976, 1514, 1260, 850 cm.sup.-1; MS (ESI): 281 (M+H).sup.+.
11. 4-(4-Methoxyphenyl)-1-(3-methoxyphenyl)-1H-imidazole
##STR00019##
[0109] Synthesis: 0.48 mmol of
4-(4-methoxyphenyl)-1-(3-methoxyphenyl)-1,3-dihydroimidazole-2-thione
is dissolved in 5 ml of cooled glacial acetic acid. 0.16 mmol of
sodium nitrite is dissolved in a 33% aqueous nitric acid solution
and slowly added dropwise to the reaction mixture over 20 minutes.
The reaction is quenched with ammonium hydroxide, the precipitate
obtained is filtered off, dried and purified by column
chromatography (ethyl acetate/methanol 2%); yield: 48%, slightly
yellow powder; Rf: (ethyl acetate): 0.44; .sup.1H NMR (CDCl.sub.3,
500 MHz): 8.90 (s, 1H, Harom) 7.60 (s, 1H, Harom), 7.53 (s, 1H,
Harom), 7.48 (m, 3H, Harom), 7.32 (t, J=7.80 Hz, 1H, Harem), 7.02
(d, J=8.50 Hz, 2H, Harom), 6.99 (dd, J=1.80 Hz and J=8.20 Hz, 1H,
Harom), 3.95 (s, 3H, OMe), 3.85 (s, 3H, OMe); .sup.13C NMR
(CDCl.sub.3, 125 MHz): 161.15, 160.55, 136.15, 133.10, 130.20,
127.20, 123.85, 117.90, 117.15, 115.85, 110.50, 56.25, 55.60; IR:
3200, 2966, 1520, 1255, 855 cm.sup.-1; MS (ESI): 281
(M+H).sup.+.
12. 1,4-Bis(4-methoxyphenyl)-1H-imidazole
##STR00020##
[0111] Synthesis: 0.67 mmol of
4-(4-methoxyphenyl)-1-(3-methoxyphenyl)-1,3-dihydroimidazole-2-thione
is dissolved in 5 ml of cooled glacial acetic acid. 0.22 mmol of
sodium nitrite is dissolved in a 33% aqueous nitric acid solution
and slowly added dropwise to the reaction mixture over 20 minutes.
The reaction is quenched with ammonium hydroxide. The precipitate
obtained is filtered off, dried and purified by column
chromatography (ethyl acetate); yield: 43%, yellow powder; Rf
(ethyl acetate): 0.60; .sup.1H NMR (CDCl.sub.3, 500 MHz): 8.05 (s,
1H, Harom) 7.70 (d, J=7.80 Hz, 2H, Harom), 7.40 (s, 1H, Harom),
7.33 (d, J=8.80 Hz, 2H, Harom), 6.97 (d, J=8.80 Hz, 2H, Harom),
6.90 (d, J=7.80 Hz, 2H, Harem), 3.83 (s, 3H, OMe), 3.79 (s, 3H,
OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz): 160.10, 115.35, 114.65,
114.55, 55.75, 55.35; IR: 2961, 2840, 1515, 1247, 1027, 828
cm.sup.-1.
13. 3-[1-(4-Hydroxyphenyl)-1H-imidazole-4-yl]phenol (4)
##STR00021##
[0113] Synthesis: Prepared from
4-(3-methoxyphenyl)-1-(4-methoxyphenyl)-1H-imidazole according to
method D. Purification: preparative thin-layer chromatography
(ethyl acetate). Yield: 28%, yellow oil; Rf (ethyl acetate): 0.55;
.sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 9.32 (d, J=1.20 Hz, 1H,
Harom), 8.33 (d, J=1.20 Hz, 1H, Harom), 7.70 (dd, J=8.80 Hz and
J=2.20 Hz, 2H, Harom), 7.33-7.36 (m, 2H, Harom), 7.29 (t, J=1.90
Hz, 1H, Harom), 7.06 (dd, J=8.80 Hz and J=2.20 Hz, 2H, Harom), 6.99
(m, 1H, Harom). .sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 159.70,
158.95, 134.95, 131.60, 129.10, 128.10, 124.95, 118.25, 117.95,
117.80, 117.35, 113.35; IR: 3563, 1684, 1629, 1048, 836 cm.sup.-1;
MS (ESI): 253: (M)..sup.+.
14. 3-[4-(4-Hydroxyphenyl)-1H-imidazole-4-yl]phenol (5)
##STR00022##
[0115] Synthesis: Prepared from
4-(4-methoxyphenyl)-1-(3-methoxyphenyl)-1H-imidazol according to
method D. Purification: preparative thin-layer chromatography
(ethyl acetate). Yield: 26%, yellow oil; Rf (ethyl acetate): 0.52;
.sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 9.50 (d, J=1.50 Hz, 1H,
Harom), 8.40 (d, J=1.50 Hz, 1H, Harom), 7.77 (m, 2H, Harom), 7.50
(t, J=8.20 Hz, 1H, Harom), 7.34-7.36 (m, 2H, Harom), 7.16 (dd,
J=2.20 Hz and J=8.80 Hz, 1H, Harom), 7.04 (dt, J=2.20 Hz and J=8.20
Hz, 2H, Harom); .sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 137.45,
132.50, 128.80 (2C), 118.35, 117.50, 114.35, 110.70; IR: 3542,
3160, 2955, 1699, 1630, 1062, 841 cm.sup.-1; MS (ESI): 253:
(M)..sup.+.
15. 4.4'-Bis-(1H-imidazole-1,4-diyl)diphenol (6)
##STR00023##
[0117] Synthesis: Prepared from
1,4-bis(4-methoxyphenyl)-1H-imidazole according to method D.
Purification: preparative thin-layer chromatography (ethyl
acetate). Yield: 26%, yellow powder; Rf (ethyl acetate): 0.57;
.sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 9.43 (d, J=1.5 Hz, 1H,
Harom), 8.32 (d, J=1.50 Hz, 1H, Harom), 7.74 (dd, J=8.80 Hz and
J=2.20 Hz, 2H, Harom), 7.71 (dd, J=8.80 Hz and J=2.20 Hz, 2H,
Harom), 7.10 (dd, J=8.80 Hz and J=2.20 Hz, 2H, Harom), 7.08 (dd,
J=8.80 Hz and J=-2.20 Hz, 2H, Harom). .sup.13C NMR
(CD.sub.3COCD.sub.3, 125 MHz): 160.40, 128.70 (2C), 125.30, 117.70
(2C), 117.45 (2C), 117.25; IR: 3563, 3155, 1684, 1048, 931, 836
cm.sup.-1; MS (ESI): 253: (M)..sup.+.
6. 2-Azido-1-(3-methoxyphenyl)ethanone
##STR00024##
[0119] Synthesis: 3.50 mmol of 3-methoxyphenacylbromide is
dissolved in 3 ml of DMF. 17.12 mmol of sodium azide is added to
the reaction mixture and stirred at room temperature for 18 h. The
solution is then poured on ice, stirred for one hour, filtered, the
residue is additionally washed with 50 ml of water and dried over
night in a desiccator. Yield: 90%, red solid; Rf (ethyl acetate):
0.55; .sup.1H NMR (CDCl.sub.3, 500 MHz): 7.42-7.44 (m, 2H, Harom),
7.38 (t, J=7.80 Hz, 1H, Harom), 7.15 (ddd, J=8.20 Hz J=2.50 Hz and
J=1.00 Hz, 1H, Harom), 4.53 (s, 2H, CO--CH.sub.2), 3.85 (s, 3H,
--OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz): 193.05, 160.10, 135.70,
129.95, 120.60, 120.30, 112.25, 55.50, 54.95; IR: 2966, 2838, 2105,
1697, 1257, 779, 685 cm.sup.-1.
17. 2-(3-Methoxyphenyl)-2-oxoethananium chloride
##STR00025##
[0121] Synthesis: 8.90 mmol of 2-azido-1-(3-methoxyphenyl)ethanone
is dissolved in 5 ml of absolute ethanol. 3.12 mmol of Lindiar
catalyst is added and stirred under a hydrogen atmosphere for 6
hours. The mixture is filtered and 8.90 mmol of 1 M hydrochloric
acid in ether solution is added dropwise to the filtrate. The
hydrochloride formed is filtered off. Yield: 13%, white powder; Rf
(CTZZ): 0.32; .sup.1H NMR (CD.sub.3SOCD.sub.3, 500 MHz): 8.5 (s,
3H, NH.sub.3.sup.+, Cl.sup.-), 7.61 (dd, J=0.90 Hz and J=7.80 Hz,
1H, Harom), 7.50-7.53 (m, 2H, Harom), 7.31 (m, 1H, Harom), 4.58 (d,
J=4.40 Hz, 2H, CO--CH.sub.2), 3.85 (s, 3H, OMe). .sup.13C NMR
(CD.sub.3SOCD.sub.3, 125 MHz): 192.75, 159.50, 135.00, 130.20,
120.55, 120.45, 112.65, 55.50, 44.85. IR: 2876, 2630, 1695, 1585,
1454, 1272, 984, 784 cm.sup.-1.
18. 3-Methoxy-N-[2-(4-methoxyphenyl)-2-oxo-ethyl]benzamide
##STR00026##
[0123] Synthesis: 4.90 mmol of
2-(4-methoxyphenyl)-2-oxoethanaminium chloride, 4.90 mmol of
3-methoxybenzoyl chloride and 9.80 mmol of triethylamine are
stirred in 3 ml of dry ether at room temperature for 8 h. The
reaction mixture is filtered and water is added to the filtrate.
The precipitate formed is filtered off and dried over night in a
desiccator. Yield: 95%, yellow powder; Rf (hexane/ethyl acetate
5:5): 0.26; .sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 8.10-8.05
(dt, J=1.50 Hz and J=7.80 Hz, 1H, Harom), 7.58 (t, J=7.80 Hz, 1H),
7.51 (m, 1H, Harom), 7.20-7.18 (ddd, J=0.60 Hz and J=2.50 Hz and
J=8.80 Hz, 1H, Harom), 6.70 (dd, J=2.20 Hz and J=8.80 Hz, 2H,
Harom), 6.53 (dd, J=2.20 Hz and J=8.80 Hz, 2H, Harom), 4.54 (s, 2H,
CO--CH.sub.2--N), 3.85 (s, 3H, --OMe), 3.83 (s, 3H, --OMe);
.sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 196.20, 193.40, 162.00,
152.45, 141.45, 136.35, 129.85, 120.15, 118.10, 117.00, 114.35,
111.25, 55.80, 55.50, 45.50; IR: 3427, 2985, 2840, 1735, 1241,
1038, 840, 755 cm.sup.-1.
19. 3-Methoxy-N[2-(4-methoxyphenyl)-2-oxoethyl]benzamide
##STR00027##
[0125] Synthesis: 4.90 mmol of
2-(3-methoxyphenyl)-2-oxoethanaminium chloride, 4.90 mmol of
4-methoxybenzoyl chloride and 9.80 mmol of triethylamine are
stirred in 3 ml of dry eher at room temperature for 8 hours. The
reaction mixture is filtered and water is added to the filtrate.
The precipitate formed is filtered off and dried over night in a
desiccator. Yield: 91%, yellow solid; Rf (hexane/ethyl acetate
5:5): 0.24; .sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 8.08-8.04
(dt, J=1.50 Hz and J=7.80 Hz, 1H, Harom), 7.51 (t, J=7.80 Hz, 1H),
7.47 (m, 1H, Harom), 7.20-7.18 (ddd, J=0.60 Hz and J=2.50 Hz and
J=8.80 Hz, 1H, Harom), 6.75 (dd, J=2.20 Hz and J=8.80 Hz, 2H,
Harom), 6.53 (dd, J=2.20 Hz and J=8.80 Hz, 2H, Harom), 4.57 (s, 2H,
CO--CH.sub.2--N), 3.83 (s, 3H, --OMe), 3.80 (s, 3H, --OMe);
.sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 196.10, 193.40, 161.80,
152.45, 141.50, 135.35, 129.95, 121.15, 118.10, 117.20, 114.15,
111.05, 55.90, 55.80, 46.10; IR: 3017, 2982, 2800, 1733, 1251,
1038, 840 cm.sup.-1.
20. 4-Methoxy-N-2-(4-methoxyphenyl)-2-oxoethyl]benzamide
##STR00028##
[0127] Synthesis: 4.90 mmol of
2-(4-methoxyphenyl)-2-oxoethanaminium chloride, 4.90 mmol of
4-methoxybenzoyl chloride and 9.80 mmol of triethylamine are
stirred in 3 ml of dry ether at room temperature for 18 h. The
reaction mixture is filtered and water is added to the filtrate.
The precipitate formed is filtered off and dried over night in a
desiccator. Yield 93%; white powder; Rf (hexane/ethyl acetate 5:5):
0.28; NMR (CD.sub.3COCD.sub.3, 500 MHz): 8.05 (d, J=7.80 Hz, 2H,
Harom), 7.93 (d, J=7.80 Hz, 2H, Harom), 7.77 (s, 1H, NH), 7.06 (d,
J=7.80 Hz, 2H, Harom), 7.00 (d, J=7.80 Hz, 2H, Harom), 4.84 (d,
J=4.40 Hz, 2H, --CO--CH.sub.2--N), 3.90 (s, 3H, --OMe), 3.86 (s,
3H, --OMe); .sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 195.20,
192.60, 164.40, 164.45, 133.45, 132.15, 129.60 (2C), 114.15 (2C),
114.10 (2C), 54.80, 53.60, 45.40; IR: 3423, 2988, 2840, 1735, 1680,
1241, 1032, 833, 750 cm.sup.-1.
21. 2,5-Bis(4-methoxyphenyl)oxazole
##STR00029##
[0129] Synthesis: 0.50 mmol of
4-methoxy-N-2-(4-methoxyphenyl)-2-oxoethyl]-benzamide is admixed
with 3 ml of concentrated sulfuric acid and heated to boiling for
24 h. The reaction mixture is immersed in an ice bath, and a 1 M
hydrochloric acid solution is added dropwise (to pH 7). The
precipitate obtained is filtered off and dried over night in a
desiccator. Yield 85%, white solid; Rf (hexane/ethyl acetate 5:5):
0.55; .sup.1H NMR (CD.sub.3SOCD.sub.3, 500 MHz): 8.05 (d, J=2.50
Hz, 1H, Harom), 7.98 (d, J=8.80 Hz, 2H, Harom), 7.96 (dd, J=2.50 Hz
and J=8.50 Hz, 1H, Harom), 7.58 (s, 1H, Harom), 7.11 (m, 3H,
Harom), 3.83 (s, 3H, --OMe), 3.82 (s, 3H, --OMe); .sup.13C NMR
(CD.sub.3SOCD.sub.3, 125 MHz): 160.95, 159.70, 156.35, 150.20,
136.10, 127.45, 127.45, 124.20, 122.25, 119.60, 114.60 (2C),
112.55, 55.70, 55.35; IR: 2947, 2843, 1646, 1485, 1253, 1098, 828
cm.sup.-1; MS (ESI): 281: (M)..sup.+.
22. 5-(4-Methoxyphenyl)-2-(3-methoxyphenyl)oxazole
##STR00030##
[0131] Synthesis: 1.16 mmol of
3-methoxy-N-[2-(4-methoxyphenyl)-2-oxoethyl]-benzamide, 12 ml of
phosphorus oxychloride are heated to boiling in 20 ml of pyridine
for 8 hours. The reaction mixture is placed into ice and diluted
with 40 ml of ethyl acetate. Thereafter, it is poured into a
saturated sodium hydrogencarbonate solution and extracted twice
with ethyl acetate. The organic phases are dried over magnesium
sulfate, filtered and purified by column chromatography
(hexane/ethyl acetate 5:5); yield: 36%; white-yellowish oil; Rf:
(hexane/ethyl acetate 5:5): 0.42; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 7.79 (d, J=8.80 Hz, 2H, Harom), 7.70 (dt, J=1.00 Hz and
J=8.80 Hz, 1H, Harom), 7.64 (q, J=1.00 Hz, 1H, Harom), 7.53 (s, 1H,
Hoxazole), 7.44 (t, J=7.90 Hz, 1H, Harom), 7.08 (m, 3H, Harom),
3.90 (s, 3H, OMe), 3.86 (s, 3H, OMe); .sup.13C NMR
(CD.sub.3COCD.sub.3, 125 MHz): 161.05, 160.95, 152.40, 130.95,
129.85, 126.65, 123.15, 121.65, 119.15, 116.95, 115.40, 111.85,
55.75, 55.70; IR: 2937.1612, 1253, 1010, 872 cm.sup.-1.
23. 4,4'-(1,3-Oxazole-2,5-diyl)diphenol (7)
##STR00031##
[0133] Synthesis: 0.18 mmol of 2,5-bis(4-methoxyphenyl)oxazole and
4.68 mmol of pyridinium hydrochloride are heated at 220.degree. C.
for 18 hours. After cooling to room temperature, 10 ml of water and
10 ml of ethyl acetate are added. The aqueous phase is washed twice
with ethyl acetate, and the combined organic phases are dried over
sodium sulfate, the solvent is filtered off and purified by
preparative thin-layer chromatography (hexane/ethyl acetate: 5/5);
yield: 82%, yellow solid; Rf (hexane/ethyl acetate 5/5): 0.30;
.sup.1H NMR (CD.sub.3OD, 500 MHz): 7.89 (d, J=7.80 Hz, 2H, Harom),
7.60 (d, J=8.80 Hz, 2H, Harom), 7.32 (s, 1H, Harom), 6.86-6.91 (m,
4H, Harom); .sup.13C NMR (CD.sub.3OD, 125 MHz): 162.35, 161.30,
159.35, 152.78, 132.80, 129.00 (2C), 126.80 (2C), 125.80 (2C),
116.90 (2C); IR: 3387, 1611, 1506, 1170, 834 cm.sup.-1. MS (ESI):
254: (M+H).sup.+.
24. 3-[5-(4-Hydroxyphenyl)-1,3-oxazole-2-yl]phenol (8)
##STR00032##
[0135] Synthesis: Prepared from 0.35 mmol of
2-(3-methoxyphenyl)-5-(4-methoxy-phenyl)oxazole according to method
E. Purification: preparative thin-layer chromatography
(hexane/ethyl acetate 5:5); yield: 65%, yellow solid; Rf
(hexane/ethyl acetate 5/5): 0.38; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.80 (s, 1H, OHarom), 8.75 (s, 1H, OHarom), 7.69 (d,
J=8.20 Hz, 2H, Harom), 7.60 (m, 2H, Harom), 7.46 (s, 1H, Hoxazole),
7.35 (t, J=8.20 Hz, 1H, Harom), 6.98-6.95 (m, 3H, Harom). .sup.13C
NMR (CD.sub.3COCD.sub.3, 125 MHz): 160.90, 158.95, 158.75, 152.55,
130.95, 129.80, 126.80, 122.50, 120.65, 118.25 (2C), 118.15,
116.85, 115.40, 113.55, IR: 3480, 1602, 1510, 852 cm.sup.-1. MS
(ESI): (M-H).sup.+: 252.
25. 4-(3-Methoxyphenyl)-2-(4-methoxyphenyl)oxazole
##STR00033##
[0137] Synthesis: 3.33 mmol of 3-methoxyacetophenone, 3.99 mmol of
HDNIB (hydroxy(2,4-dinitrobenzenesulfonyloxy)iodo)benzene) in
acetonitrile are heated to reflux for 2 h. The reaction mixture is
briefly cooled down to room temperature, and 9.99 mmol of
4-methoxybenzonitrile is added, followed by heating under reflux
for 10 h. Acetonitrile is evaporated, and the solid is dissolved in
dichloromethane. The organic phase is then washed with a saturated
sodium hydrogencarbonate solution, dried over magnesium sulfate and
purified by column chromatography (hexane/ethyl acetate 7:3). Yield
50%, white powder; Rf (hexane/ethyl acetate 6:4): 0.55; .sup.1H NMR
(CD.sub.3COCD.sub.3, 500 MHz): 8.23 (s, 1H, Hoxazole), 7.90 (d,
J=9.20 Hz, 2H, Harom), 7.32 (m, 2H, Harom), 7.20 (t, J=7.50 Hz, 1H,
Harom), 6.93 (d, J=9.20 Hz, 2H, Harom), 6.76 (1H, Harom), 3.73 (s,
3H, OMe), 3.70 (s, 3H, OMe); IR: 3015, 2925, 1625, 789
cm.sup.-1.
26. 3-[4-(4-Hydroxyphenyl)-1,3-oxazole-2-yl]phenol (9)
##STR00034##
[0139] Synthesis: Prepared from 0.21 mmol of
4-(3-methoxyphenyl)-2-(4-methoxyphenyl)oxazole according to method
E, purification: column chromatography (hexane/ethyl acetate 5:5);
Rf (hexane/ethyl acetate 6:4): 0.62; .sup.1H NMR
(CD.sub.3COCD.sub.3, 500 MHz): 8.27 (s, 1H, Hoxazole), 7.93 (d,
J=8.50 Hz, 2H, Harom), 7.37 (s, 1H, Harom), 7.33 (d, J=7.60 Hz, 1H,
Harom), 7.20 (t, J=7.60 Hz, 1H, Harom), 6.97 (d, J=8.50 Hz, 2H,
Harom), 6.79 (m, 1H, Harom); .sup.13C NMR (CD.sub.3COCD.sub.3, 125
MHz): 161.80, 159.70, 157.75, 141.55, 133.70, 132.90, 129.70;
128.05, 119.25, 116.70, 115.75, 114.90, 112.35; IR: 3300, 1595,
1259, 804 cm.sup.-1; MS (ESI): (M-H).sup.+: 282.
27. 2-(3-Methoxyphenyl)-5-(4-methoxyphenyl)-1H-imidazole
##STR00035##
[0141] Synthesis: 0.20 mmol of
3-methoxy-N-2-(4-methoxyphenyl)-2-oxoethyl]benzamide and 1.60 mmol
of ammonium acetate are dissolved in 15 ml of glacial acetic acid
and heated to reflux for 2 h. The solvent is then evaporated, the
solid is dissolved in ethanol and water, and 50 ml of
dichloromethane is added. The organic phases are washed with a
saturated sodium chloride solution, dried over magnesium sulfate
and purified by column chromatography (hexane/ethyl acetate 5:5);
yield: 6%, yellow solid; Rf (hexane/ethyl acetate 5:5): 0.48; NMR
(CDCl.sub.3, 500 MHz): 8.04 (s, 1H, Harom), 7.85 (d, J=8.20 Hz, 2H,
Harom), 7.28-7.24 (m, 3H, Harom), 6.88 (d, J=8.20 Hz, 2H, Harom),
6.78 (dq, J=7.60 Hz and J=1.50 Hz, 1H, Harom), 3.79 (s, 3H, OMe),
3.77 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz): 164.00,
132.35 (2C), 130.15, 120.60, 119.85, 113.75, 112.65, 55.60, 55.50;
IR: 3077, 2965, 1678, 1468, 1240, 1031, 742 cm.sup.-1; MS (ESI):
281: (M)..sup.-.
28. 2-(4-Methoxyphenyl)-5-(3-methoxyphenyl)-1H-imidazole
##STR00036##
[0143] Synthesis: 0.20 mmol of
4-methoxy-N-2-(3-methoxyphenyl)-2-oxoethyl]benzamide and 1.6 mmol
of ammonium acetate are dissolved in 15 ml of glacial acetic acid
and heated to reflux for 2 hours. The solvent is then evaporated,
the solid is dissolved in ethanol and water, and 50 ml of
dichloromethane is added. The organic phases are washed with
saturated sodium chloride solution, dried over magnesium sulfate
and purified by column chromatography (hexane/ethyl acetate 5:5);
yield: 25%, white Solid; Rf (hexane/ethyl acetate: 5/5): 0.45;
.sup.1H NMR (CD.sub.3SOCD.sub.3, 500 MHz): 8.07 (d, J=2.50 Hz, 1H,
Harom), 7.98 (d, J=8.50 Hz, 2H, Harom), 7.78 (d, J=8.50 Hz, 1H,
Harom), 7.57 (s, 1H, Harom), 7.37 (s, 1H, Harom), 7.12-7.08 (m, 3H,
Harom), 6.75 (s, 1H, Harom), 3.83 (s, 3H, OMe), 3.82 (s, 3H, OMe);
.sup.13C NMR (CD.sub.3SOCD.sub.3, 125 MHz): 162.10, 160.85, 151.40,
137.50, 128.65 (2H), 127.25, 125.40, 123.35, 120.75, 115.75 (2C),
113.70, 56.80, 56.50; IR: 3070, 2950, 1578, 1242, 742 cm.sup.-1; MS
(ESI): 281: (M)..sup.+.
29. 2,5-Bis(4-methoxyphenyl)-1H-imidazole
##STR00037##
[0145] Synthesis: 0.20 mmol of
4-methoxy-N-2-(4-methoxyphenyl)-2-oxo-ethyl]benzamide and 1.60 mmol
of ammonium acetate are dissolved in 15 ml of glacial acetic acid
and heated to reflux for 2 hours. The solvent is then evaporated,
and the solid is dissolved in ethanol and water, and 50 ml of
dichloromethane was added. The organic phases are washed with
saturated sodium chloride solution, dried over magnesium sulfate
and purified by column chromatography (hexane/ethyl acetate 5:5);
yield: 32%, yellow solid; Rf (hexane/ethyl acetate): 0.51; .sup.1H
NMR (CD.sub.3COCD.sub.3, 500 MHz): 8.03 (d, J=9.10 Hz, 2H, Harom),
7.80 (d, J=8.50 Hz, 2H, Harom), 7.43 (s, 1H, Harom), 7.02 (d,
J=8.80 Hz, 2H, Harom), 6.95 (d, J=9.10 Hz, Harom), 3.84 (s, 3H,
OMe), 3.81 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz):
161.00, 159.45, 145.05, 130.35, 129.00 (2C), 128.00 (2C), 121.25,
117.75 (2C), 114.00 (2C), 55.70, 55.20; IR: 1672, 1394, 1149, 874
cm.sup.-1.
30. 3-[2-(4-Hydroxyphenyl)-1H-imidazole-5-yl]phenol (10)
##STR00038##
[0147] Synthesis: Prepared from 0.14 mmol of
2-(3-methoxyphenyl)-5-(4-methoxyphenyl)-1H-imidazole according to
method D. Purification: preparative thin-layer chromatography
(hexane/ethyl acetate: 5/5); yield: 45%, yellow solid; Rf
(hexane/ethyl acetate 5:5): 0.58; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.58 (s, 1H, Harom), 7.42 (t, J=7.80 Hz, 2H, Harom), 7.42
(m, 1H, Harom), 7.33 (m, 1H, Harom), 7.27 (t, J=7.80 Hz, 2H,
Harom), 7.05 (dd, J=0.90 Hz and J=1.50 Hz, 1H, Harom), 6.90 (dd,
J=0.90 Hz and J=1.50 Hz, 1H, Harom), 6.47 (s, 1H, N--H arom);
.sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 168.95, 168.90, 158.25,
137.90, 136.95, 130.10 (2C), 119.40, 119.10, 118.70, 115.25; IR:
3450, 2950, 1604, 1580, 785 cm.sup.-1. MS (ESI): (M+H).sup.+:
253.
31. 3-[5-(4-Hydroxyphenyl)-1H-imidazole-2-yl]phenol (11)
##STR00039##
[0149] Synthesis: Prepared from 0.14 mmol of
2-(4-methoxyphenyl)-5-(3-methoxyphenyl)-1H-imidazole according to
method D. Purification: preparative thin-layer chromatography
(hexane/ethyl acetate: 5/5); yield: 42%, yellow solid; Rf
(hexane/ethyl acetate 5:5): 0.58; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.56 (s, 1H, Harom), 7.40 (t, J=7.80 Hz, 2H, Harom), 7.39
(m, 1H, Harom), 7.37 (m, 1H, Harom), 7.25 (t, J=7.80 Hz, 2H,
Harom), 6.99 (dd, J=0.90 Hz and J=1.50 Hz, 1H, Harom), 6.97 (dd,
J=0.90 Hz and J=1.50 Hz, 1H, Harom), 6.47 (s, 1H, N-Harom);
.sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 168.95, 168.90, 158.25,
137.95, 136.90, 130.15 (2C), 119.30 (2C), 118.95, 115.40; IR: 3350,
3045, 2922, 1664, 1582, 760 cm.sup.-1. MS (ESI): (M+H).sup.+:
253.
32. 4,4'-(1H-Imidazole-2,5-diyl)diphenol (12)
##STR00040##
[0151] Synthesis: Prepared from 0.29 mmol of
2-(4-methoxyphenyl)-5-(3-methoxyphenyl)-1H-imidazole according to
method D. Purification: preparative thin-layer chromatography
(dichloromethane/methanol 1%); yield: 17%, yellow-brown solid; Rf
(ethyl acetate): 0.30; .sup.1H NMR (CD.sub.3OD, 500 MHz): 7.83 (d,
J=8.70 Hz, 2H, Harom), 7.62 (d, J=8.70 Hz, 2H, Harom), 7.60 (s, 1H,
Harom), 7.03 (d, J=8.70 Hz, 2H, Harom), 6.92 (d, J=8.70 Hz, 2H,
Harom); .sup.13C NMR (CD.sub.3OD, 125 MHz): 131.30, 129.15, 120.15,
120.15, 119.80, 119.80, 115.55 (2C), 114.75 (2C), 114.30; IR: 2590,
1645, 1488, 1114, 841 cm.sup.-1; MS (ESI): 253:(M+H).sup.+.
33. 1-(3-Methoxyphenyl)-3-(4-methoxyphenyl)propenone
##STR00041##
[0153] Synthesis: To a freshly prepared sodium ethanolate solution,
7.30 mmol of 3-methoxyacetophenone and 7.30 mmol of
4-methoxybenzaldehyde are added at room temperature and stirred for
2 hours. The ethanol is evaporated, and the reaction mixture is
purified by column chromatography (hexane/ethyl acetate 7:3);
yield: 33%, yellow oil; Rf (hexane/ethyl acetate 5:5): 0.72;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 7.61-7.58 (d, J=15.40 Hz, 1H,
Hethylen), 7.42 (d, J=8.80 Hz, 2H, Harom), 7.38-7.36 (m, 3H,
Harom), 7.24-7.20 (d, J=15.40 Hz, 1H, Hethylen), 7.18 (t, J=8.10
Hz, 1H, Harom), 6.91 (dd, J=8.10 Hz and J=2.00 Hz, 1H, Harom), 6.71
(d, J=8.80 Hz, 2H, Harom), 3.64 (s, 3H, OMe), 3.58 (s, 3H, OMe);
.sup.13C NMR (CDCl.sub.3, 125 MHz): 190.90, 162.75, 160.90, 145.60,
140.90, 131.30 (2C), 130.55, 128.60, 122.00, 120.65, 119.90 (2C),
114.00, 56.35, 56.30; IR: 1735, 1658, 1571, 1280, 1170, 1025, 791
cm.sup.-1.
34. 1-(4-Methoxyphenyl)-3-(3-methoxyphenyl)propenone
##STR00042##
[0155] Synthesis: To a freshly prepared sodium ethanolate solution,
7.30 mmol of 3-methoxyacetophenone and 7.30 mmol of
4-methoxybenzaldehyde are added at room temperature and stirred for
2 hours. The ethanol is evaporated, and the reaction mixture is
purified by column chromatography (hexane/ethyl acetate 7:3);
yield: 75%; white powder; Rf (hexane/ethyl acetate 5:5): 0.89;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 8.00 (d, J=8.80 Hz, 2H, Harom),
7.74-7.70 (d, J=15.50 Hz, 1H, Hethylen), 7.50-7.46 (d, J=15.50 Hz,
1H, Hethylen), 7.29 (t, J=8.10 Hz, 1H, Harom), 7.21 (d, J=8.10 Hz,
1H, Harom), 7.11 (m, 1H, Harom), 6.96-6.94 (m, 3H, Harom), 3.85 (s,
3H, OMe), 3.82 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz):
189.05, 163.70, 160.15, 144.15, 136.65, 131.25 (2C), 130.10,
122.45, 121.20, 116.30 (2C), 114.05, 113.65, 58.40, 55.70; IR:
1657, 1592, 1251, 1166, 1018, 830 cm.sup.-1.
35. 1,3-Bis(4-methoxyphenyl)propenone
##STR00043##
[0157] Synthesis: To a freshly prepared sodium ethanolate solution,
7.30 mmol of 3-methoxyacetophenone and 7.30 mmol of
4-methoxybenzaldehyde are added at room temperature and stirred for
2 hours. The ethanol is evaporated, and the reaction mixture is
purified by column chromatography (hexane/ethyl acetate 7:3);
yield: 98%, white powder; Rf (hexane/ethyl acetate 5:5): 0.80;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 8.05 (d, J=8.80 Hz, 2H, Harom),
7.75 (d, J=15.50 Hz, 1H, Hethylen), 7.48 (d, J=15.50 Hz, 1H,
Hethylen), 7.30 (d, J=8.80 Hz, 2H, Harom), 7.19 (d, J=8.20 Hz, 2H,
Harom), 6.89 (d, J=8.20 Hz, 2H, Harom), 3.84 (s, 3H, OMe), 3.79 (s,
3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz): 189.20, 162.70,
160.10, 145.20, 131.10 (2C), 130.20, 122.60, 121.10, 117.10,
116.30, 114.05, 113.65, 58.60, 55.80; IR: 2980, 1687, 1552, 1251,
850 cm.sup.-1.
36. 3,5-Bis(4-methoxyphenyl)-1H-pyrazole
##STR00044##
[0159] Synthesis: 0.94 mmol of
1,3-bis(4-methoxyphenyl)propane-1,3-dione is dissolved in a THF/DMF
mixture (1:3). 0.94 mmol of hydrazine monohydrate is added dropwise
and heated to reflux for 18 hours. After cooling to room
temperature, 10 ml of a saturated lithium chloride solution and 10
ml of ethyl acetate are added. The organic phase is washed with
saturated sodium chloride solution, dried over magnesium sulfate
and concentrated. 0.94 mmol of a 1 M hydrochloric acid solution in
ether is added. The precipitate formed is subjected to suction
filtration and washed with ether. Yield: 91%, white powder; Rf
(ethyl acetate): 0.48, .sup.1H NMR (CDCl.sub.3, 500 MHz): 7.79 (d,
J=8.20 Hz, 4H, Harom), 7.09 (s, 1H, Harom), 7.03 (d, J=8.20 Hz, 4H,
Harom), 3.80 (s, 6H, OMe). .sup.13C NMR (CDCl.sub.3, 125 MHz):
159.55, 127.00, 114.45, 98.80, 55.40, IR: 3009, 2944, 2577, 1619,
1518, 1265, 803 cm.sup.-1.
37. 3-(4-Methoxyphenyl)-5-(3-methoxyphenyl)pyrazole
##STR00045##
[0161] Synthesis: 0.93 mmol of
1-(4-methoxyphenyl)-3-(3-methoxyphenyl) propenone is dissolved in
ethanol. 3.72 mmol of hydrazine monohydrate and 3.72 mmol of
glacial acetic acid are added dropwise. The mixture is heated to
reflux for 24 hours. After cooling to room temperature, the
precipitate is filtered off. Water and ethyl acetate are added to
the filtrate. The organic phase is washed with saturated sodium
chloride solution, dried over magnesium sulfate and purified first
by column chromatography (hexane/ethyl acetate 5:5) and then by
preparative thin-layer chromatography (dichloromethane/methanol
1%). Yield: 25%, yellow oil; Rf (dichloromethane/methanol 1%):
0.18; .sup.1H NMR (CDCl.sub.3, 500 MHz): 7.55 (d, J=8.80 Hz, 2H,
Harom), 7.21-7.19 (m, 2H, Harom), 7.18 (t, J=7.80 Hz, 1H, Harom),
6.78-6.75 (m, 3H, Harom), 6.62 (s, 1H, Harom), 3.74 (s, 3H, OMe),
3.62 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz): 159.85,
159.55, 129.70, 126.85, 126.85, 118.10, 114.15 (2C), 114.10,
110.50, 99.35, 55.20, 55.05; IR: 2933, 2837, 1601, 1439, 1250,
1033, 834 cm.sup.-1.
38. 3-(3-Methoxyphenyl)-5-(4-methoxyphenyl)pyrazole
##STR00046##
[0163] Synthesis: 1.03 mmol of
2,3-dibromo-1-(3-methoxyphenyl)-3-(4-methoxyphenyl)propenone is
dissolved in ethanol. 4.12 mmol of hydrazine monohydrate and 4.12
mmol of glacial acetic acid are added dropwise. The mixture is
heated under reflux for 24 hours. After cooling to room
temperature, the precipitate is filtered off. Water and ethyl
acetate are added to the filtrate. The organic phase is washed with
a saturated sodium chloride solution, dried over magnesium sulfate
and purified by column chromatography (hexane/ethyl acetate 5:5);
yield: 16%, white solid; Rf (hexane/ethyl acetate 5:5): 0.70;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 7.96 (d, J=8.80 Hz, 2H, Harom),
7.67 (t, J=2.30 Hz, 1H, Harom), 7.50 (d, J=7.80 Hz, 1H, Harom),
7.38 (t, J=7.80 Hz, 1H, Harom), 7.02-6.99 (m, 3H, Harom), 6.88 (s,
1H, Harom), 3.92 (s, 3H, OMe), 3.84 (s, 3H, OMe); .sup.13C NMR
(CDCl.sub.3, 125 MHz): 161.80, 160.30, 147.60, 130.35, 128.90,
127.20, 119.50, 117.85, 114.80 (2C), 111.90, 109.80, 100.23, 55.90,
55.45; IR: 1611, 1480, 1258, 1022, 818 cm.sup.-1.
39. 4,4'-(1H-Pyrazole-3,5-diyl)diphenol (13)
##STR00047##
[0165] Synthesis: Prepared from 0.25 mmol of
3-(3-methoxyphenyl)-5-(4-methoxyphenyl)pyrazole according to method
E. Purification: preparative thin-layer chromatography:
(dichloromethane/methanol 8%). Yield: 55%, yellow powder; .sup.1H
NMR (CD.sub.3OD, 500 MHz): 8.59 (d, J=8.50 Hz, 4H, Harom), 7.84 (d,
J=8.50 Hz, 4H, Harom), 7.76 (s, 1H, Harom); .sup.13C NMR
(CD.sub.3OD, 125 MHz): 159.50, 150.50, 128.60, 124.10, 117.00,
99.80, 80.60, 69.50; IR: 3400, 3200, 1613, 1509, 1460 cm.sup.-1; MS
(ESI): 253.
40. 3-[3-(4-Hydroxyphenyl)-1H-pyrazole-5-yl]phenol (14)
##STR00048##
[0167] Synthesis: Prepared from 0.25 mmol of
3-(3-methoxyphenyl)-5-(4-methoxyphenyl)pyrazole according to method
E. Purification: preparative thin-layer chromatography:
(dichloromethane/methanol 8%). Yield: 55%, orange powder; Rf (D/M
8%): 0.25; .sup.1H NMR (CD.sub.3OD, 500 MHz): 7.65 (d, J=8.50 Hz,
2H, Harom), 7.22 (m, 1H, Harom), 6.83 (d, J=8.50 Hz, 2H, Harom),
6.81 (s, 1H, Harom), 6.72-6.74 (m, 3H, Harom); .sup.13C NMR
(CD.sub.3OD, 125 MHz): 160.50, 131.85, 122.10, 122.10, 117.05,
116.80, 116.00, 113.30 (2C), 102.15; IR: 3500, 2935, 1620, 790
cm.sup.-1; MS (ESI): (M+H).sup.+: 253.
41. 3-[5-(4-Hydroxyphenyl)-1H-pyrazole-3-yl]phenol (15)
##STR00049##
[0169] Synthesis: Prepared from 0.157 mmol of
3-(3-methoxyphenyl)-5-(4-methoxyphenyl)pyrazole according to method
E. Purification: preparative thin-layer chromatography:
(dichloromethane/methanol 10 Ws). Yield: 39%, orange powder; Rf
(D/M 10%): 0.42; .sup.1H NMR (CD.sub.3OD, 500 MHz): 7.62 (d, J=8.50
Hz, 2H, Harom), 7.24-7.21 (m, 3H, Harom), 6.85 (d, J=8.50 Hz, 2H,
Harom), 6.79 (s, 1H, Harom), 6.78-6.76 (m, 1H, Harom); .sup.13C NMR
(CD.sub.3OD, 125 MHz): 159.00, 130.85, 128.10, 128.10, 118.05,
116.65, 116.10, 113.55 (2C), 100.05; IR: 3411, 2925, 1614, 1459,
785 cm.sup.-1; MS (ESI): (M+H).sup.+: 253.
42.
2,3-Dibromo-1-(3-methoxyphenyl)-3-(4-methoxyphenyl)propan-1-one
##STR00050##
[0171] Synthesis: 1.03 mmol of
1-(3-methoxyphenyl)-3-(4-methoxyphenyl) propenone is dissolved in 5
ml of absolute ether and placed in an ice bath. 1.03 mmol of
bromine is diluted in 2 ml of absolute ether and added dropwise to
the mixture. After about 1 h, the yellow precipitate is filtered
off and washed with ether. Yield: 97%, white solid; Rf
(hexane/ethyl acetate 5:5): 0.80; .sup.1H NMR (CDCl.sub.3, 500
MHz): 7.65 (d, J=8.20 Hz, 1H, Harom), 7.59 (t, J=2.30 Hz, 1H,
Harom), 7.44-7.41 (m, 3H, Harom), 7.19-7.17 (dd, J=8.20 Hz and
J=2.30 Hz, 1H, Harom), 6.92 (d, J=8.80 Hz, 2H, Harom), 5.76 (d,
J=11.40 Hz, 1H, CH--Br), 5.63 (d, J=11.40 Hz, 1H, CH--Br), 3.88 (s,
3H, OMe), 3.82 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz):
191.20, 160.20, 160.15, 135.90, 130.30, 129.90, 129.65 (2C),
121.25, 120.70, 114.25 (2C), 113.30, 55.55, 55.35, 50.25, 47.25;
IR: 2966, 2840, 1684, 1597, 1254, 1022, 756 cm.sup.-1.
43.
2,3-Dibromo-1-(4-methoxyphenyl)-3-(3-methoxyphenyl)propane-1-one
##STR00051##
[0173] Synthesis: 0.93 mmol of
1-(3-methoxyphenyl)-3-(4-methoxyphenyl) propenone is dissolved in 5
ml of carbon tetrachloride and placed in an ice bath. 0.93 mmol of
bromine is diluted in 2 ml of carbon tetrachloride and added
dropwise to the mixture. After about 1.5 h, the solvent is
evaporated. Yield: 96%, brown oil; Rf (dichloromethane): 0.72;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 8.06 (d, J=9.10 Hz, 2H, Harom),
7.31 (t, J=7.90 Hz, 1H, Harom), 7.11 (d, J=7.90 Hz, 1H, Harom),
7.03 (t, J=1.80 Hz, 1H, Harom), 6.99 (d, J=9.10 Hz, 2H, Harom),
6.89 (dd, J=7.88 Hz and J=1.80 Hz, 1H, Harom), 5.75 (d, J=11.40 Hz,
1H, CH--Br), 5.60 (d, J=11.40 Hz, 1H, CH--Br), 3.89 (s, 3H, OMe),
3.84 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz): 189.65,
164.45, 159.70, 140.00, 131.35 (2C), 129.85, 127.25, 120.65,
114.50, 114.30, 114.25, 55.65, 55.35, 49.90, 46.70; IR: 1675, 1597,
1255, 1028, 844 cm.sup.-1.
44. 3,5-Bis(4-methoxyphenyl)isoxazole
##STR00052##
[0175] Synthesis: 4 mmol of
1,3-bis(4-methoxyphenyl)-1,3-propanedione is stirred under reflux
with 4.20 mmol of hydroxylamine hydrochloride and 10 ml of absolute
ethanol for 7 hours. After cooling to room temperature, the
reaction mixture is poured in 50 ml of water. The precipitate
formed is filtered off, washed with cool water, dried and purified
by column chromatography (hexane/ethyl acetate 9:1); yield: 97%,
slightly yellow powder; Rf (hexane/ethyl acetate: 8:2); .sup.1H NMR
(CDCl.sub.3, 500 MHz): 7.83 (s, 1H, Hisoxazol), 7.80 (d, J=8.80 Hz,
2H, Harom), 7.78 (d, J=9.10 Hz, 2H, Harom), 7.00 (d, J=9.20 Hz, 2H,
Harom), 6.96 (d, J=8.80 Hz, 2H Harom), 3.87 (s, 3H, Harom), 3.85
(s, 3H, Harom); .sup.13C NMR (CDCl.sub.3, 500 MHz): 146.60, 131.80,
128.10, 129.90, 114.10, 54.00, 52.20; IR: 2920, 1603, 1501, 1254,
850 cm.sup.-1.
45. 3-(3-Methoxyphenyl)-5-(4-methoxyphenyl)isoxazole
##STR00053##
[0177] Synthesis: 0.90 mmol of
2,3-dibromo-1-(3-methoxyphenyl)-3-(4-methoxyphenyl)propane-1-one is
stirred under reflux with 0.90 mmol of hydroxylamine hydrochloride
and 10 ml of absolute ethanol for 24 hours. After cooling to room
temperature, the reaction mixture is poured in 50 ml of water. The
aqueous phase is extracted with ethyl acetate, and the resulting
organic phases are washed with a saturated sodium chloride
solution, dried over magnesium sulfate and purified by column
chromatography (hexane/ethyl acetate 7:3); yield: 12%, slightly
yellow solid; Rf (hexane/ethyl acetate 5:5): 0.72; .sup.1H NMR
(CDCl.sub.3, 500 MHz): 7.76 (d, J=8.20 Hz, 2H, Harom), 7.41-7.38
(m, 3H, Harom), 6.98-6.96 (m, 3H, Harom), 6.67 (s, 1H, Harom), 3.86
(s, 3H, OMe), 3.85 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3, 125
MHz): 170.40, 162.85, 161.15, 160.00, 130.55, 129.90, 127.45,
127.45, 120.30, 119.30, 116.05 (2C), 114.45, 111.75, 96.25, 55.40;
IR: 3003, 2927, 2837, 1613, 1473, 1253, 1177, 836 cm.sup.-1.
46. 2-(1H-1,2,3-Benzotriazole-1-yl)-1-(4-methoxyphenyl)ethanone
##STR00054##
[0179] Synthesis: 4.40 mmol of benzotriazole is dissolved in 2 ml
of anhydrous THF and cooled in an ice bath. 4.40 mmol of sodium
hydride is added in several small portions. After 45 minutes, 4.40
mmol of 4-methoxyphenacyl bromide is added and stirred at room
temperature for 18 hours. The raw product is washed with water and
thereafter with a saturated sodium chloride solution, dried over
magnesium sulfate and purified by column chromatography
(hexane/ethyl acetate 9:1). Yield: 55%, white powder; Rf
(hexane/ethyl acetate 5:5): 0.38; .sup.1H NMR (CDCl.sub.3, 500
MHz): 8.09 (d, J=8.20 Hz, 1H, Harom), 8.00 (d, J=9.15 Hz, 2H,
Harom), 7.45-7.38 (m, 2H, Harom), 7.36-7.34 (m, 1H, Harom), 7.95
(d, J=9.15 Hz, 2H, Harom), 6.00 (s, 2H, CH.sub.2--CO), 3.86 (s, 3H,
OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz): 189.80, 165.60, 147.15,
134.90, 131.75, 131.75, 128.75 (2C), 128.10, 125.00, 121.10,
115.40, 110.70, 56.65, 54.65; IR: 2966, 2931, 1688, 1601, 1239,
1169, 824, 756 cm.sup.-1.
47.
2-(1H-1,2,3-Benzotriazole-1-yl)-1-(3-methoxyphenyl)-3-(4-methoxyphenyl-
)prop-2-ene-1-one
##STR00055##
[0181] Synthesis: 0.56 mmol of
2-(1H-1,2,3-benzotriazole-1-yl)-1-(3-methoxyphenyl)ethanone and
0.56 mmol of 4-methoxybenzaldehyde are dissolved in 5 ml of
ethanol. 0.28 mmol of piperidine is added to the reaction mixture
and stirred at room temperature for 48 hours. The raw product is
poured in water/ethyl acetate (1:1). The water phase is washed with
ethyl acetate, the resulting organic phases are washed with a
saturated sodium chloride solution, dried over magnesium sulfate
and purified by column chromatography (hexane/ethyl acetate 9:1).
Yield: 51%, yellow oil; Rf (hexane/ethyl acetate 5:5): 0.25;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 8.04 (d, J=7.80 Hz, 1H, Harom),
7.75 (s, 1H, Harom), 7.31-7.29 (m, 3H, Harom), 7.21 (t, J=7.55 Hz,
1H, Harom), 7.19 (m, 2H, Harom), 7.00-6.95 (m, 1H, Harom), 6.66 (d,
J=8.82 Hz, 2H, Harom), 6.58 (d, J=8.82 Hz, 2H, Harom), 3.66 (s, 3H,
OMe9, 3.62 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz):
189.95, 161.30, 158.65, 144.85, 141.60, 137.30, 132.30, 131.65,
131.65, 128.55, 127.35, 123.30, 120.45, 119.15 (2C), 118.05, 113.55
(2C), 112.40, 109.05; IR: 1655, 1595, 1259, 1175, 745
cm.sup.-1.
48. 5-(3-Methoxyphenyl)-3-(4-methoxyphenyl)isoxazole
##STR00056##
[0183] Synthesis: 0.28 mmol of
2-(1H-1,2,3-benzotriazole-1-yl)-1-4-(4-methoxyphenyl)-3-(3-methoxyphenyl)-
prop-2-ene-1-one and 0.56 mmol of hydroxylamine hydrochloride are
stirred under reflux. After 18 hours, the reaction mixture is
poured on a mixture of water/ethyl acetate (1:1). The aqueous phase
is washed with ethyl acetate, the resulting organic phases are
washed with a saturated sodium chloride solution, dried over
magnesium sulfate and purified first by column chromatography
(hexane/ethyl acetate 9:1) and then by preparative thin-layer
chromatography (dichloromethane/methanol 1%); yield: 45%, yellow
powder; Rf (dichloromethane/methanol 1%): 0.41; .sup.1H NMR
(CDCl.sub.3, 500 MHz): 7.20 (m, 2H, Harom), 6.75 (dd, J=7.50 Hz and
J=2.00 Hz, 1H, Harom), 6.80 (d, J=7.50 Hz, 1H, Harom), 6.76 (s, 1H,
Harom), 6.74 (s, 1H, Harom), 6.70 (m, 1H, Harom), 6.45 (d, J=7.50
Hz, 2H, Harom), 3.72 (s, 3H, OMe), 3.56 (s, 3H, OMe); .sup.13C NMR
(CDCl.sub.3, 125 MHz): 171.65, 164.15, 162.40, 161.25, 131.80,
131.20, 128.70, 128.70, 121.60, 120.60, 117.35, 115.70, 113.00,
97.50; IR: 2925, 2853, 1602, 1248, 746 cm.sup.-1.
49. 4,4'-Isoxazole-3,5-diyldiphenol (16)
##STR00057##
[0185] Synthesis: Prepared from 1.00 mmol of
3,5-bis(4-methoxyphenyl) isoxazole according to method E.
Purification: column chromatography (hexane/ethyl acetate: 4:6);
yield: 93%, yellow solid; Rf (dichloromethane/methanol 9:1): 0.73;
.sup.1H NMR (CD.sub.3OD, 500 MHz): 8.70-8.72 (m, 4H, Harom), 7.92
(s, 1H, Harom), 7.89 (m, 4H, Harom); .sup.13C NMR (CD.sub.3OD, 125
MHz): 172.10, 164.50, 161.10, 160.80, 132.60, 130.00, 129.50,
128.70, 121.70, 117.10, 116.90, 96.80; IR: 3321, 1610, 1509, 1443,
850 cm.sup.-1; MS (ESI): (M+H).sup.+: 254.
50. 3-[5-(4-Hydroxyphenyl)isoxazole-3-yl]phenol (17)
##STR00058##
[0187] Synthesis: Prepared from 0.16 mmol of
3-(3-methoxyphenyl)-5-(4-methoxyphenyl)isoxazole according to
method E. Purification: preparative thin-layer chromatography:
(dichloromethane/methanol 5%). Yield: 36%, yellow powder; Rf
(dichloromethane/methanol 9:1): 0.62; .sup.1H NMR (CD.sub.3OD, 500
MHz): 7.89 (s, 1H, Harom), 7.42 (d, J=8.50 Hz, 2H, Harom),
7.20-7.17 (m, 3H, Harom), 6.93 (d, J=8.50 Hz, 2H, Harom), 6.77 (m,
1H, Harom); .sup.13C NMR (CD.sub.3OD, 125 MHz): 164.50, 162.00,
130.90, 128.20 (2C), 118.05, 116.65, 116.20, 115.55 (2C), 98.90;
IR: 3369, 2905, 1652, 859 cm.sup.-1; MS (ESI): (M+H).sup.+:
254.
51. 3-[3-(4-Hydroxyphenyl)isoxazole-5-yl]phenol (18)
##STR00059##
[0189] Synthesis: Prepared from 0.80 mmol of
5-(3-methoxyphenyl)-3-(4-methoxyphenyl)isoxazole according to
method E. Purification: preparative thin-layer chromatography:
(dichloromethane/methanol 5%). Yield: 36%, yellow powder; Rf
(dichloromethane/methanol 9:1): 0.64; .sup.1H NMR (CD.sub.3OD, 500
MHz): 7.85 (s, 1H, Harom), 7.32 (d, J=8.50 Hz, 2H, Harom),
7.10-7.07 (m, 3H, Harom), 7.05m, 1H, Harom), 6.90 (d, J=8.50 Hz,
2H, Harom); .sup.13C NMR (CD.sub.3OD, 125 MHz): 165.60, 164.90,
138.20, 126.20, 126.20, 118.05, 118.05, 112.60, 115.80, 115.70,
98.80; IR: 3409, 2905, 1652, 870 cm.sup.-1; MS (ESI): (M+H).sup.+:
254.
52. 5-Bromo-2-(3-methoxyphenyl)thiazole
##STR00060##
[0191] Synthesis: Prepared from 2.06 mmol of 2,5-dibromothiophene
and 2.47 mmol of 3-methoxyphenylboronic acid according to method A,
purification: column chromatography (dichloromethane/methanol 5%);
yield: 50%, yellow solid; Rf (dichloromethane): 0.82; .sup.1H NMR
(CDCl.sub.3, 500 MHz): 7.45 (s, 1H, Harom), 7.16 (s.1H, Harom),
7.13 (dt, J=1.20 Hz and J=8.20, Hz, 1H, Harom), 7.05 (t, J=8.20 Hz,
8.20 Hz), 6.70 (m, 1H, Harom), 3.59 (s, 3H, OMe); .sup.13C NMR
(CDCl.sub.3, 125 MHz): 159.00, 128.90, 123.10, 117.30, 112.00,
110.30, 54.30. IR: 2985, 1485, 992, 837 cm.sup.-1.
53. 5-Bromo-2-(4-methoxyphenyl)thiazole
##STR00061##
[0193] Synthesis: Prepared from 2.06 mmol of 2,5-dibromothiophene
and 2.47 mmol of 4-methoxyphenylboronic acid according to method A,
purification: column chromatography (dichloromethane/methanol 5%);
yield: 50%, yellow solid; yield: 65%, yellow solid; Rf
(hexane/ethyl acetate 7:3): 0.61; .sup.1H NMR (CDCl.sub.3, 500
MHz): 7.52 (d, J=8.50 Hz, 2H, Harom), 7.39 (s, 1H, Hthiazole), 6.66
(d, J=8.50 Hz, 2H, Harem), 3.57 (s, 3H, OMe); .sup.13C NMR
(CDCl.sub.3, 125 MHz): 168.35, 160.35, 142.95 (2C), 134.75, 127.00
(2C), 113.35, 54.35; IR: 1934, 2837, 1603, 1240, 1170, 827
cm.sup.-1.
54. 5-(4-Methoxyphenyl)-2-(3-methoxyphenyl)thiazole
##STR00062##
[0195] Synthesis: Prepared from 0.68 mmol of
5-bromo-2-(3-methoxyphenyl) thiazole and 1.37 mmol of
4-methoxyphenylboronic acid according to method A, purification:
column chromatography (hexane/ethyl acetate: [0196] 9:1); yield:
58%, yellow oil; Rf (hexane/ethyl acetate 7:3): 0.58; .sup.1H NMR
(CDCl.sub.3, 500 MHz): 7.89 (s, 1H, Hthiazole), 7.51-7.49 (m, 4H,
Harom), 7.32 (t, J=7.90 Hz, 1H, Harom), 6.93-6.91 (m, 3H, Harom),
3.86 (s, 3H, OMe), 3.82 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3, 125
MHz): 165.20, 159.05, 158.85, 138.35, 137.05, 128.95, 127.00 (2C),
117.95, 115.30, 113.55, 109.75, 54.75, 54.40; IR: 2980, 1580, 1240,
830 cm.sup.-1.
55. 5-(3-Methoxyphenyl)-2-(4-methoxyphenyl)thiazole
##STR00063##
[0198] Synthesis: Prepared from 0.95 mmol of
5-bromo-2-(3-methoxyphenyl) thiazole and 1.37 mmol of
4-methoxyphenylboronic acid according to method A, purification:
column chromatography (hexane/ethyl acetate: 9:1); yield: 50%,
yellow oil; Rf (hexane/ethyl acetate 7:3): 0.60; .sup.1H NMR
(CDCl.sub.3, 500 MHz): 7.98 (s, 1H, Hthiazole), 7.53 (d, J=8.50 Hz,
2H, Harom), 7.51 (d, J=8.50 Hz, 2H, Harom), 7.33 (t, J=7.80 Hz, 1H,
Harom), 7.19 (d, J=7.80 Hz, 1H, Harom), 7.11 (t, J=2.50 Hz, 1H,
Harom), 6.85 (m, 1H, Harom), 3.87 (s, 3H, OMe), 3.84 (s, 3H, OMe);
.sup.13C NMR (CDCl.sub.3, 125 MHz): 165.20; 159.05, 158.85, 138.35,
137.05, 128.95, 127.00 (2C), 117.95, 115.30, 113.55, 109.75, 54.75,
54.40; IR: .delta. 2978, 1602, 1238, 852 cm.sup.-1.
56. 2,5-Bis-(4-methoxyphenyl)thiazole
##STR00064##
[0200] Synthesis: Prepared from 2.06 mmol of 2,5-dibromothiazole
and 4.94 mmol of 4-methoxyphenylboronic acid according to method A,
purification: column chromatography (dichloromethane/methanol 5%);
yield: 10%, yellow solid; Rf (hexane/ethyl acetate 7:3): 0.45;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 7.94 (s, 1H, Hthiazole), 7.74
(d, J=8.82 Hz, 2H, Harom), 6.95-6.90 (m, 4H, Harom), 3.83 (s, 3H,
OMe), 3.82 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz):
160.90, 158.90, 150.25, 137.00 (2C), 135.60, 127.25 (2C), 122.70,
113.80, 113.25, 112.45, 54.40, 54.15; IR: 2980, 1605, 1250, 837
cm.sup.-1; MS (ESI): (M+H).sup.+: 298.
57. 2,5-Bis(3-methoxyphenyl)thiazole
##STR00065##
[0202] Synthesis: Prepared from 2.06 mmol of 2,5-dibromothiazole
and 4.94 mmol of 4-methoxyphenylboronic acid according to method A,
purification: column chromatography (hexane/ethyl acetate 9:1);
yield: 40%, yellow oil; Rf (hexane/ethyl acetate 8:2): 0.38;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 7.99 (s, 1H, Hthiazole), 7.55
(s, 1H, Harom), 7.51 (d, J=8.20 Hz. 1H, Harom), 7.34-7.31 (m, 2H,
Harom), 7.17 (d, J=8.20 Hz, 1H, Harom), 7.10 (s, 1H, Harom), 6.97
(dd, J=8.20 Hz and J=2.50 Hz, 1H, Harom), 6.89 (J=8.20 Hz and
J=2.50 Hz, 1H, Harom), 3.87 (s, 3H, OMe), 3.85 (s, 3H, OMe);
.sup.13C NMR (CDCl.sub.3, 125 MHz): 160.10, 130.20, 130.05, 119.15,
116.80, 113.95, 112.40, 110.95, 55.50, 55.40; IR: 2984, 1608, 865
cm.sup.-1,
58. 3-[5-(4-Hydroxyphenyl)-1,3-thiazole-2-yl]phenol (19)
##STR00066##
[0204] Synthesis: Prepared from 0.13 mmol of
5-(4-methoxyphenyl)-2-(3-methoxyphenyl)thiazole according to method
E, purification: column chromatography (hexane/ethyl acetate 5:5);
yield: 80%, yellow solid; Rf (hexane/ethyl acetate 5:5): 0.52;
.sup.1H NMR (CD.sub.3OD, 500 MHz): 7.80 (s, 1H, Hthiazole), 7.39
(d, J=8.80 Hz, 2H, Harom), 7.30 (m, 2H, Harom), 7.19 (t, J=8.20 Hz,
1H, Harom), 6.80-6.74 (m, 3H, Harom); .sup.13C NMR (CD.sub.3OD, 125
MHz): 167.70, 159.35, 159.25, 141.35, 138.25, 135.85, 131.25 (2C),
129.05, 123.60, 118.60, 118.30, 117.05 (2C), 113.80; IR: 3351,
2927, 1607, 1457, 830 cm.sup.-1; MS (ESI): (M+H).sup.+: 270.
59. 3-[2-(4-Hydroxyphenyl)-1,3-thiazole-5-yl]phenol (20)
##STR00067##
[0206] Synthesis: Prepared from 0.13 mmol of
5-(3-methoxyphenyl)-2-(4-methoxyphenyl)thiazole according to method
E, purification: column chromatography (hexane/ethyl acetate 5:5);
yield: 77%, yellow solid; Rf (H/E 5:5): 0.65. .sup.1H NMR
(CD.sub.3OD, 500 MHz): 8.01 (s, 1H, Hthiazole), 7.39 (m, 2H,
Harom), 7.28 (m, 2H, Harom), 7.13 (d, J=7.80 Hz, 1H Harom), 7.07
(s, 1H, Harom), 6.88 (d, J=7.80 Hz, 1H, Harom), 6.78 (d, J=7.80 Hz,
1H, Harom); .sup.13C NMR (CD.sub.3OD, 125 MHz): 168.80, 159.30,
140.95, 139.70, 135.75, 133.45, 131.40 (2C), 131.20, 118.85,
118.85, 118.70, 116.70, 114.25, 113.90; IR: 3367, 2925, 2854, 1454,
1032, 750 cm.sup.-1; MS (ESI): (M+H).sup.+: 270.
[0207] 60. 4,4'-(1,3-Thiazole-2,5-diyl)diphenol (21)
##STR00068##
[0208] Synthesis: Prepared from 0.13 mmol of
5-(3-methoxyphenyl)-2-(4-methoxyphenyl)thiazole according to method
E, purification: column chromatography (hexane/ethyl acetate 5:5);
yield: 95%, yellow oil; Rf (hexane/ethyl acetate 5:5): 0.50;
.sup.1H NMR (CD.sub.3OD, 500 MHz): 7.73 (s, 1H, Hthiazole), 7.66
(d, J=8.80 Hz, 2H, Harom), 7.37 (d, J=8.80 Hz, 2H, Harom),
6.77-6.73 (m, 4H, Harom); .sup.13C NMR (CD.sub.3OD, 125 MHz):
168.25, 160.95, 159.20, 140.10, 137.85, 133.05, 129.95, 128.95,
128.90, 117.00, 116.90; IR: 3500, 1609, 1455, 836 cm.sup.-1; MS
(ESI): (M+H).sup.+: 270.
61. 4,4'-(1,3-Thiazole-2,5-diyl)diphenol (22)
##STR00069##
[0210] Synthesis: Prepared from 0.51 mmol of
5-(3-methoxyphenyl)-2-(4-methoxyphenyl)thiazole according to method
E, purification: preparative thin-layer chromatography
(hexane/ethyl acetate 5:5); yield: 85%, yellow oil; Rf
(hexane/ethyl acetate 5:5): 0.42; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.62 (s, 2H, OH), 8.11 (s, 1H, Hthiazole), 7.52 (t,
J=2.50 Hz, 1H, Harom), 7.48 (m, 1H, Harom), 7.34 (t, J=7.80 Hz, 1H,
Harom), 7.28 (t, J=7.80 Hz, 1H, Harom), 7.19-7.16 (m, 2H, Harom),
6.97 (m, 1H, Harom), 6.87 (m, 1H, Harom); .sup.13C NMR
(CD.sub.3COCD.sub.3, 125 MHz): 158.95, 158.85, 140.35, 140.00,
135.90, 133.45, 131.25, 131.1.0, 118.75, 118.50, 118.15, 116.40,
114.15, 113.60; IR: 3517, 1695, 1453, 1242, 866 cm.sup.-1; MS
(ESI): (M+H).sup.+: 270.
62. 4-Bromo-2-(3-methoxyphenyl)thiazole
##STR00070##
[0212] Synthesis: Prepared from 2.06 mmol of 2.4-dibromothiazole
and 2.47 mmol of 3-methoxyphenylboronic acid according to method A,
purification: column chromatography (hexane/ethyl acetate 9:1);
yield: 50%, yellow oil; Rf (dichloromethane): 0.78; .sup.1H NMR
(CDCl.sub.3, 500 MHz): 7.50 (t, J=2.50 Hz, 1H, Harom), 7.48 (dt,
J=7.80 Hz and J=2.50 Hz, 1H, Harom), 7.34 (t, J=7.80 Hz, 1H,
Harom), 7.20 (s, 1H, Hthiazole), 7.00-6.98 (m, 1H, Harom), 3.86 (s,
3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz): 167.80, 159.00,
132.75, 129.00, 124.90, 117.80, 115.95, 115.55, 110.00, 54.45; IR:
3118, 2935, 2835, 1598, 1458, 1252, 1015, 782 cm.sup.-1.
63. 4-Bromo-2-(4-methoxyphenyl)thiazole
##STR00071##
[0214] Synthesis: Prepared from 2.06 mmol of 2,4-dibromothiazole
and 2.47 mmol of 4-methoxyphenylboronic add according to method A,
purification: column chromatography (hexane/ethyl acetate 9:1);
yield: 55%, yellow solid; Rf (dichloromethane): 0.78; NMR
(CDCl.sub.3, 500 MHz): 7.84 (d, J=8.80 Hz, 2H, Harom), 7.10 (s, 1H,
Hthiazole), 6.91 (d, J=8.80 Hz, 2H, Harom), 3.82 (s, 3H, OMe);
.sup.13C NMR (CDCl.sub.3, 125 MHz): 167.85, 161.00, 126.85, 124.65,
124.50, 114.35, 113.30, 54.40; IR: 3114, 1603, 1466, 1258, 825
cm.sup.-1.
64. 4-(4-Methoxyphenyl)-2-(3-methoxyphenyl)thiazole
##STR00072##
[0216] Synthesis: Prepared from 0.55 mmol of
4-bromo-2-(3-methoxyphenyl) thiazole and 0.77 mmol of
4-methoxyphenylboronic acid according to method A, purification:
column chromatography (hexane/ethyl acetate 9:1); yield: 79%, white
solid; Rf (hexane/ethyl acetate 9:1): 0.45; .sup.1H NMR
(CDCl.sub.3, 500 MHz): 7.93 (d, J=8.80 Hz, 2H, Harom), 7.62 (s, 1H,
Harom), 7.61 (d, J=7.88 Hz, 1H, Harom), 7.36 (t, J=7.88 Hz, 1H,
Harom), 7.30 (s, 1H, Hthiazole), 6.98-6.96 (m, 3H, Harom), 3.88 (s,
3H, Harom), 3.83 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz):
166.45, 159.00, 158.65, 155.00, 134.10, 128.90, 127.00 (2C),
118.15, 115.00, 113.05 (2C), 110.45, 109.95, 54.40, 54.30; IR:
3108, 2961, 2837, 1596, 1481, 1249, 1173, 1036, 834 cm.sup.-1.
65. 4-(3-Methoxyphenyl)-2-(4-methoxyphenyl)thiazole
##STR00073##
[0218] Synthesis: Prepared from 0.55 mmol of
4-bromo-2-(4-methoxyphenyl) thiazole and 0.77 mmol of
4-methoxyphenylboronic acid according to method A, purification:
column chromatography (hexane/ethyl acetate 9:1); yield: 65%,
yellow solid; Rf (hexane/ethyl acetate 5:5): 0.62; .sup.1H NMR
(CDCl.sub.3, 500 MHz): 7.97 (d, J=8.80 Hz, 2H, Harom), 7.59 (s.1H,
Harom), 7.55 (dt, J=2.50 Hz and J=7.25 Hz. 1H, Harom), 7.37 (s, 1H,
Harom), 7.34 (t, J=7.25 Hz, 1H, Harom), 6.95 (d, J=8.80 Hz, 2H,
Harom), 6.90 (m, 1H, Harom), 3.87 (s, 3H, OMe), 3.83 (s, 3H, OMe);
.sup.13C NMR (CDCl.sub.3, 125 MHz): 166.65, 160.15, 158.95, 154.80,
134.95, 128.95, 128.65 (2C), 127.05, 125.70, 117.85, 113.30 (2C),
112.00, 111.05, 54.35, 54.30; IR: 2954, 1596, 1250, 855
cm.sup.-1.
66. 2,4-Bis(4-methoxyphenyl)thiazole
##STR00074##
[0220] Synthesis, physical and chemical characterization already
described by Fink, B. E., et al., Chem. and Biol., 6: 205-219
(1999).
67. 2,4-Bis(4-methoxyphenyl)thiazole
##STR00075##
[0222] Synthesis: Prepared from 2.06 mmol of 2,4-dibromothiazole
and 4.94 mmol of 3-methoxyphenylboronic acid according to method A,
purification: column chromatography (hexane/ethyl acetate 9:1);
yield: 18%, yellow oil; Rf (hexane/ethyl acetate 8:2): 0.40;
.sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 7.92 (s, 1H, Hthiazole),
7.65-7.59 (m, 4H, Harom), 7.35 (t, J=7.90 Hz, 1H, Harom), 7.33 (t,
J=7.90 Hz, 1H, Harom), 7.05 (m, 1H, Harom), 6.93 (m, 1H, Harom),
3.87 (s, 3H, OMe), 3.85 (s, 3H, OMe); .sup.13C NMR
(CD.sub.3COCD.sub.3, 125 MHz): 160.35, 160.25, 130.20, 129.75,
118.75, 118.65, 115.90, 113.65, 111.85, 111.40, 54.85, 54.70; IR:
3012, 2929, 1642, 1250, 812 cm.sup.-1.
68. 3-[4-(4-Hydroxyphenyl)-1,3-thiazole-2-yl]phenol (23)
##STR00076##
[0224] Synthesis: Prepared from 0.30 mmol of
4-(4-methoxyphenyl)-2-(3-methoxyphenyl)thiazole according to method
E, purification: preparative thin-layer chromatography
(hexane/ethyl acetate 5:5); yield: 80%, yellow oil; Rf
(hexane/ethyl acetate 5:5): 0.45; .sup.1H NMR (CD.sub.3OD, 500
MHz): 7.71 (d, J=8.80 Hz, 2H, Harom), 7.39 (s, 1H, Hthiophene),
7.36 (s, 1H, Harom), 7.34 (d, J=7.80 Hz, 1H, Harom), 7.17 (t,
J=7.80 Hz, 1H, Harom), 6.76-6.74 (m, 3H, Harom); .sup.13C NMR
(CD.sub.3OD, 125 MHz): 169.30, 159.15, 158.85, 157.70, 136.25,
131.20, 129.20, 128.95, 127.70, 118.90, 118.25, 116.75, 116.50,
114.10, 112.00; IR: 3671, 2988, 1609, 1480, 970, 836 cm.sup.-1; MS
(ESI): (M-H).sup.+: 268.
69. 3-[2-(4-Hydroxyphenyl)-1,3-thiazole-4-yl]phenol (24)
##STR00077##
[0226] Synthesis: Prepared from 0.30 mmol of
4-(3-methoxyphenyl)-2-(4-methoxyphenyl)thiazole according to method
E, purification: preparative thin-layer chromatography
(hexane/ethyl acetate 5:5); yield: 78%, yellow oil; Rf
(hexane/ethyl acetate 5:5): 0.52; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.87 (s, 1H, OH), 8.40 (s, 1H, OH), 7.93 (d, J=8.80 Hz,
2H, Harom), 7.91 (s, 1H, Hthiazole), 7.73 (s, 1H, Harom), 7.60 (d,
J=7.80 Hz, 1H, Harom), 7.25 (t, J=7.80 Hz, 1H Harem), 6.96 (d,
J=8.80 Hz, 2H, Harom), 6.83 (m, 1H, Harem); .sup.13C NMR
(CD.sub.3COCD.sub.3, 125 MHz): 170.95, 168.35, 160.35, 158.65,
156.55, 137.00, 130.55, 128.90, 126.60, 118.45, 116.70, 115.90,
114.20, 112.90; IR: 3351, 2962, 1689, 1587, 836 cm.sup.-1; MS
(ESI): (M-H).sup.+: 268.
70. 4,4'-(1,3-Thiazole-2,4-diyl)diphenol (25)
##STR00078##
[0228] Synthesis, physical and chemical characterization already
described by Fink, B. E., et al., Chem. and Biol., 6: 205-219
(1999).
71. 3,3'-(1,3-Thiazole-2,4-diyl)diphenol (26)
##STR00079##
[0230] Synthesis: Prepared from 0.24 mmol of
2,4-bis(3-methoxyphenyl)thiazole according to method E,
purification: preparative thin-layer chromatography (hexane/ethyl
acetate 5:5); yield: 78%, yellow oil; Rf (hexane/ethyl acetate
5:5): 0.52; .sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 7.86 (s, 1H,
Hthiazole), 7.59 (m, 2H, Harom), 7.54 (m, 2H, Harom), 7.35 (t,
J=8.00 Hz, 1H, Harom), 7.29 (t, J=8.00 Hz, 1H, Harom), 6.97 (m, 1H,
Harom), 6.85 (m, 1H, Harom); .sup.13C NMR (CD.sub.3COCD.sub.3, 125
MHz): 159.85, 158.85, 135.95, 135.05, 130.20, 129.70, 117.70,
117.25, 115.10, 112.35; IR: 3312, 1635, 1622, 759 cm.sup.-1; MS
(ESI): (M-H).sup.+: 268.
72. 2-Bromo-5-(4-methoxyphenyl)thiophene
##STR00080##
[0232] Synthesis: Prepared from 2.1 mmol of 2,5-dibromothiophene
and 2.52 mmol of 4-methoxyphenylboronic acid according to method C,
purification: column chromatography (hexane/ethyl acetate 9:1),
yield: 75%, white powder; Rf (hexane/ethyl acetate 8:2): 0.72;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 7.41 (d, J=8.80 Hz, 2H, Harom),
6.97 (d, J=3.78 Hz, 1H, Hthiophene), 6.91 (m, 3H,
2Harom+Hthiophene), 3.81 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3,
125 MHz): 158.50, 144.80, 129.70, 126.70 (2C), 121.15, 113.40,
109.15, 54.35; IR: 2955, 1606, 1501, 1252, 791 cm.sup.-1.
73. 2-(3-Methoxyphenyl)-5-(4-methoxyphenyl)thiophene
##STR00081##
[0234] Synthesis: Prepared from 0.93 mmol of
2-bromo-5-(4-methoxyphenyl) thiophene and 1.11 mmol of
3-methoxyphenylboronic acid, purification: column chromatography
(hexane/ethyl acetate 9:1), yield: 75%, yellow powder; Rf
(hexane/ethyl acetate 8:2): 0.65; .sup.1H NMR (CDCl.sub.3, 500
MHz): 7.47 (d, J=8.82 Hz, 2H, Harom), 7.20 (t, J=7.80 Hz, 1H,
Harom), 7.17 (m, 1H, Hthiophene), 7.10 (m, 1H, Harom), 7.07 (m, 2H,
Harom+Hthiophene), 6.84 (d, J=8.80 Hz, 2H, Harom), 6.76 (dd, J=7.80
Hz and J=2.50 Hz, 1H, Harom), 3.77 (s, 3H, OMe), 3.75 (s, 3H, OMe);
.sup.13C NMR (CDCl.sub.3, 125 MHz): 158.95, 158.30, 142.70, 141.30,
134.75, 128.30, 126.20, 125.95, 123.15, 121.85, 118.70, 117.20,
113.35, 111.85, 110.20, 54.35, 54.30; IR: 2934, 1575, 1463, 1242,
1032, 811 cm.sup.-1.
74. 2,5-Bis(4-methoxyphenyl)thiophene
##STR00082##
[0236] Synthesis: Prepared from 2.10 mmol of 2,5-dibromothiophene
and 2.52 mmol of 4-methoxyphenylboronic acid according to method A,
purification: column chromatography (hexane/ethyl acetate 9:1),
yield: 10%, white powder; Rf (hexane/ethyl acetate 8:2): 0.62
.sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 7.15 (d, J=8.50 Hz, 4H,
Harom), 6.90 (s, 2H, Hthiophene), 6.53 (d, J=8.50 Hz, 4H, Harom),
3.34 (s, 3H, OMe); .sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz):
158.85, 126.40, 120.40, 114.50, 55.20; IR: 2854, 1598, 758
cm.sup.-1.
75. 2,5-Bis(3-methoxyphenyl)thiophene
##STR00083##
[0238] Synthesis: Prepared from 2.10 mmol of 2,5-dibromothiophene
and 2.52 mmol of 3-methoxyphenylboronic acid according to method A,
purification: column chromatography (hexane/ethyl acetate 9:1),
yield: 8%, white powder; Rf (hexane/ethyl acetate 8:2): 0.57;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 7.28 (t, J=7.80 Hz, 2H, Harom),
7.05 (s, 2H, Harom), 7.15 (m, 2H, Harom), 7.10 (m, 2H, Harom), 6.82
(s, 2H, Hthiophene), 3.83 (s, 6H, OMe); .sup.13C NMR (CDCl.sub.3,
125 MHz): 161.00, 142.30, 133.25, 129.15, 123.85, 120.00, 118.60,
109.45, 54.50; IR: 2930, 1600, 1242, 820 cm.sup.-1.
76. 3-Bromo-2-(4-methoxyphenyl)thiophene
##STR00084##
[0240] Synthesis: Prepared according to method A from 3.01 mmol of
2,3-dibromothiophene and 3.04 mmol of 4-methoxyphenylboronic acid,
purification: column chromatography (hexane); yield: 70%, green
solid; Rf (hexane-ethyl acetate. 9:1): 0.92; .sup.1H NMR
(CD.sub.3COCD.sub.3, 500 MHz): 7.54 (d, J=9.20 Hz, 2H, Harom), 7.33
(d, J=1.30 Hz, 1H, Hthiophene), 7.22 (d, J=1.30 Hz, 1H,
Hthiophene), 6.94 (d, J=9.20 Hz, 2H, Harom), 3.77 (s, 3H, OMe);
.sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 161.00, 127.80, 126.65,
125.40, 122.25, 115.40, 110.85, 55.75; IR: 2936, 1612, 1254, 852
cm.sup.-1.
77. 3-Bromo-2-(4-methoxyphenyl)thiophene
##STR00085##
[0242] Synthesis: Prepared according to method C from 0.88 mmol of
2,3-dibromothiophene and 0.97 mmol of 3-methoxyphenylboronic acid,
purification: column chromatography (Hexan); yield: 58%, yellow
oil; Rf (hexane-ethyl acetate 9:1): 0.90; .sup.1H NMR (CDCl.sub.3,
500 MHz): 7.32 (t, J=8.20 Hz, 1H, Harom), 7.26 (d, J=5.40 Hz, 1H,
Hthiophene), 7.20 (m, 2H, Harom), 7.03 (d, J=5.40 Hz, 1H,
Hthiophene), 6.91-6.89 (m, 1H, Harom), 3.83 (s, 3H, OMe); .sup.13C
NMR (CDCl.sub.3, 125 MHz): 159.50, 138.10, 134.05, 131.70, 129.55,
125.70, 125.00, 121.50, 114.50, 114.05, 107.60, 55.35; IR: 3001,
2925, 1625, 1244, 869 cm.sup.-1.
78. 2,3-Bis(4-methoxyphenyl)thiophene
##STR00086##
[0244] Synthesis: Prepared according to method A from 0.31 mmol of
3-bromo-2-(4-methoxyphenyl)thiophene and 0.34 mmol of
4-methoxyphenylboronic acid, purification: column chromatography
(hexane); yield: 83%, yellow powder; .sup.1H NMR
(CD.sub.3COCD.sub.3, 500 MHz): 7.41 (d, J=5.00 Hz, 1H, Hthiophene),
7.22-7.19 (m, 4H, Harom), 7.14 (d, J=5.00 Hz, 1H, Hthiophene),
6.87-6.84 (m, 4H, Harom), 3.84 (s, 3H, OMe), 3.79 (s, 3H, OMe);
.sup.13C NMR (CD.sub.3COCD.sub.3, 500 MHz): 158.70, 158.20, 130.55,
129.75, 129.70, 129.45, 128.40, 128.20, 126.85, 126.25, 113.60,
113.40, 113.20, 54.10, 54.05; IR: 2952, 1612, 1253, 752
cm.sup.-1.
79. 3-(4-Methoxyphenyl)-2-(3-methoxyphenyl)thiophene
##STR00087##
[0246] Synthesis: Prepared according to method C from 1.95 mmol of
3-bromo-2-(4-methoxyphenyl)thiophene and 2.34 mmol of
4-methoxyphenyl boronic acid, purification: column chromatography
(hexane/ethyl acetate 7:3); yield 40%, white powder; Rf
(hexane/ethyl acetate 7:3): 0.35; .sup.1H NMR (CDCl.sub.3, 500
MHz): 7.22 (d, J=5.20 Hz, 1H, Hthiophene), 7.13 (d, J=8.50 Hz, 2H,
Harom), 7.03 (d, J=5.20 Hz, 1H, Hthiophene), 7.10 (t, J=7.80 Hz,
1H, Harom), 6.77 (d, J=7.80 Hz, 1H, Harom), 6.76-6.74 (m, 3H,
Harom), 6.70 (dd, J=2.50 Hz and J=7.80 Hz, 1H, Harom), 3.77 (s, 3H,
OMe), 3.59 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz):
158.40, 157.60, 136.85, 136.60, 134.80, 129.45, 129.20, 128.40,
128.05, 123.00, 120.70, 113.45, 112.80, 112.30, 54.20, 54.10; IR:
3011, 2836, 1605, 1252, 861 cm.sup.-1.
80. 4,4'-Thiene-2,3-diyldiphenol (27)
##STR00088##
[0248] Synthesis: Prepared according to method E from 1.00 mmol of
2,3-bis(4-methoxyphenyl)thiophene, purification: column
chromatography (hexane/ethyl acetate 5:5), yield: 70%, green
powder; Rf (hexane/ethyl acetate 5:5): 0.49; .sup.1H NMR
(CD.sub.3OD, 500 MHz): 7.09-7.03 (m, 5H, Harom), 6.81 (d, J=5.50
Hz, 1H, Hthiophene), 6.69-6.65 (m, 4H, Harom); .sup.13C NMR
(CD.sub.3OD, 125 MHz): 131.70, 131.55, 128.45, 123.95, 122.55,
119.10, 116.50, 116.25, 116.15, 116.10, 113.10, 108.80; MS (ESI):
269.
81. 3-[3-(4-Hydroxyphenyl)-2-thienyl]phenol (28)
##STR00089##
[0250] Synthesis: Prepared according to method E from 0.49 mmol of
3-(4-methoxyphenyl)-2-(3-methoxyphenyl)thiophene, purification:
column chromatography (hexane/ethyl acetate 5:5); yield: 56%, green
powder; Rf (H/E 5:5): 0.51; .sup.1H NMR (CD.sub.3OD, 500 MHz): 7.35
(d, J=5.50 Hz, 1H, Harom), 7.09-7.06 (m, 4H, H), 6.75-6.72 (m, 5H,
Harom); .sup.13C NMR (CD.sub.3OD, 125 MHz): 139.30, 131.90, 131.20,
130.50, 129.30, 124.80, 121.65, 117.10, 116.20, 115.35; IR: 3520,
2925, 1652, 825 cm.sup.-1. MS (ESI): (M+H).sup.+:269.
82. 3-[5-(4-Hydroxyphenyl)-2-thienyl]phenol (29)
##STR00090##
[0252] Synthesis: Prepared from 0.10 mmol of
2-(3-methoxyphenyl)-5-(4-methoxyphenyl)thiophene according to
method E, purification: preparative thin-layer chromatography
(hexane/ethyl acetate 5:5); yield: 93%, yellow powder; Rf
(hexane/ethyl acetate 5:5): 0.48; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.57 (s, 1H, OH), 8.48 (s, 1H, OH), 7.53 (d, J=8.80 Hz,
2H, Harom), 7.33 (d, J=3.78 Hz, 1H, Hthiophene), 7.25-7.20 (m, 3H,
2Harom+Hthiophene), 7.15-7.13 (m, 2H, Harom), 6.89 (d, J=8.80 Hz,
2H, Harom), 6.78 (m, 1H, Harom); .sup.13C NMR (CD.sub.3COCD.sub.3,
125 MHz): 157.90, 157.35, 143.70, 135.65, 130.05, 126.80, 124.20,
122.75, 116.60, 115.85, 114.50, 112.00; IR: 3301, 2967, 1242, 1033,
803 cm.sup.-1; MS (ESI): (M+H).sup.+:269.
83. 4,4'-Thiene-2,5-diyldiphenol (30)
##STR00091##
[0254] Synthesis: Prepared from 0.30 mmol of
2,5-bis(4-methoxyphenyl) thiophene according to method E,
purification: preparative thin-layer chromatography (hexane/ethyl
acetate 5:5); yield: 95%, yellow powder; Rf (hexane/ethyl acetate
5:5): 0.47; .sup.1H NMR (CD.sub.3COCD.sub.3, 500'MHz): 8.51 (s, 2H,
OH), 7.50 (d, J=8.80 Hz, 4H, Harom), 7.21 (s, 2H, Hthiophene), 6.89
(d, J=8.80 Hz, 4H, Harom); .sup.13C NMR (CD.sub.3COCD.sub.3, 125
MHz): 158.05, 143.20, 127.55, 127.05, 123.55, 116.70; IR: 3305,
1593, 798 cm.sup.-1; MS (ESI): 269:(M+H).sup.+.
84. 3,3'-Thiene-2,5-diyldiphenol (31)
##STR00092##
[0256] Synthesis: Prepared from 1.20 mmol of
2,5-bis(3-methoxyphenyl) thiophene according to method E,
purification: preparative thin-layer chromatography (hexane/ethyl
acetate 5:5); yield: 95%, yellow powder; Rf (hexane/ethyl acetate
5:5): 0.45; .sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 8.50 (s, 2H,
--OHArom), 7.38 (s, 2H, Harom), 7.24 (t, J=7.80 Hz, 2H, Harom),
7.17 (m, 4H, Harom), 6.81 (m, 2H, Harom); .sup.13C NMR
(CD.sub.3COCD.sub.3, 125 MHz): 158.85, 144.10, 136.35, 131.00,
125.20, 117.65, 115.65, 113.05; IR: 3325, 2985, 1489, 852
cm.sup.-1; MS (ESI): 269:(M+H).sup.+.
85. 4-Bromo-2-(4-methoxyphenyl)thiophene
##STR00093##
[0258] Synthesis: Prepared from 1.10 mmol of 2,4-dibromothiophene
and 1.23 mmol of 4-methoxyphenylboronic acid according to method C,
purification: column chromatography (hexane/ethyl acetate 9:1);
yield: 78%, white powder; Rf (hexane/ethyl acetate 8:2): 0.79;
.sup.1H NMR (CDCl.sub.3, 500 MHz):7.46 (d, J=8.82 Hz, 2H, Harom),
7.08 (d, J=1.20 Hz, 1H, Hthiophene), 7.07 (d, J=1.20 Hz, 1H,
Hthiophene), 6.90 (d, J=8.82 Hz, 2H, Harom), 3.81 (s, 3H, OMe);
.sup.13C NMR (CDCl.sub.3, 125 MHz): 159.75, 145.40, 127.10 (2C),
126.05, 124.65, 120.90, 114.40, 110.35, 55.35; IR: 2937, 1606,
1291, 745 cm.sup.-1.
86. 4-Bromo-2-(3-methoxyphenyl)thiophene
##STR00094##
[0260] Synthesis: Prepared from 1.10 mmol of 2,4-dibromothiophene
and 1.23 mmol of 3-methoxyphenylboronic acid according to method C,
purification: column chromatography (hexane/ethyl acetate 9:1);
yield: 72%, colorless oil; Rf (hexane/ethyl acetate 8:2): 0.80;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 7.31 (t, J=7.80 Hz, 1H, Harom),
7.18 (d, J=2.00 Hz, 1H, Hthiophene), 7.15 (d, J=2.00 Hz, 1H,
Hthiophene), 7.12 (m, 1H, Harom), 7.06 (m, 1H, Harom), 6.85 (dd,
J=7.80 Hz and J=2.20 Hz, 1H, Harom), 3.83 (s, 3H, OMe); .sup.13C
NMR (CDCl.sub.3, 125 MHz): 159.05, 144.30, 133.25, 129.05, 124.85,
121.00, 120.60, 117.70, 117.30, 112.75, 110.45, 109.45, 54.30; IR:
2970, 1650, 1252, 885, 770 cm.sup.-1.
87. 4-(3-Methoxyphenyl)-2-(4-methoxyphenyl)thiophene
##STR00095##
[0262] Synthesis: Prepared from 0.73 mmol of
4-bromo-2-(4-methoxyphenyl)thiophene and 0.88 mmol of
3-methoxyphenylboronic acid according to method C, purification:
column chromatography (hexane/ethyl acetate 9:1); yield: 70%,
slightly yellowish powder; Rf (hexane/ethyl acetate 8:2): 0.68;
.sup.1H NMR (CD.sub.3OD, 500 MHz): 7.51-7.48 (m, 3H,
2Harom+1Hthiophene), 7.38 (d, J=1.25 Hz, 1H, Hthiophene), 7.20 (t,
J=7.80 Hz, 1H, Harom), 7.14 (m, 1H, Harom), 7.09 (m, 1H, Harom),
6.84 (d, J=8.80 Hz, 2H, Harom), 6.74 (m, 1H, Harom). .sup.13C NMR
(CD.sub.3OD, 125 MHz): 173.00, 158.85, 158.55, 146.50, 144.30,
138.60, 130.85, 128.40, 128.10, 127.95, 127.45, 121.85, 119.25,
118.65, 116.75, 115.15, 114.00; IR: 3305, 2835, 1612, 750
cm.sup.-1; MS (ESI): (M-H).sup.+: 267.
88. 4-(4-Methoxyphenyl)-2-(3-methoxyphenyl)thiophene
##STR00096##
[0264] Synthesis: Prepared from 3.01 mmol of
4-bromo-2-(3-methoxyphenyl)thiophene and 3.60 mmol of
4-methoxyphenylboronic acid according to method C, purification:
column chromatography (hexane/ethyl acetate 9:1); yield: 22%,
slightly yellowish powder; Rf (hexane/ethyl acetate 7:3): 0.48;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 7.42 (m, 3H,
2Harom+1Hthiophene), 7.19 (t, J=7.88 Hz, 1H, Harom), 7.13 (d,
J=1.50 Hz, 1H, Hthiophene), 7.07 (m, 1H, Harom), 6.82 (d, J=8.50
Hz, 2H, Harom), 6.74 (m, 1H, Harom), 3.73 (s, 3H, OMe), 3.70 (s,
3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz): 159.00, 157.95,
143.70, 141.70, 134.90, 128.90, 127.65, 126.40, 121.40, 117.40,
113.15, 112.10, 110.50, 54.25, 54.20; IR: 2965, 1605, 1491, 1252,
1030, 826 cm.sup.-1.
89. 2,4-Bis(3-methoxyphenyl)thiophene
##STR00097##
[0266] Synthesis: Prepared from 1.03 mmol of
4-bromo-2-(3-methoxyphenyl)thiophene and 3.66 mmol of
3-methoxyphenylboronic acid according to method C, purification:
column chromatography (hexane/ethyl acetate 9:1); yield: 72%,
slightly yellowish powder; Rf (hexane/ethyl acetate 8:2): 0.68;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 7.47 (d, J=1.50 Hz, 1H,
Hthiophene), 7.27 (d, J=1.50 Hz, 1H, Hthiophene), 7.20 (t, J=7.80
Hz, 2H, Harom), 7.15-7.12 (m, 2H, Harom), 7.13-7.10 (m, 2H, Harom),
6.77-6.75 (m, 2H, Harom), 3.76 (s, 6H, OMe); .sup.13C NMR
(CDCl.sub.3, 125 MHz): 159.00, 143.85, 141.90, 136.25, 134.60,
128.95, 128.80, 121.55, 118.95, 117.85, 117.45, 112.20, 111.60,
111.15, 110.50, 54.30; IR: 2938, 1580, 1165, 777 cm.sup.-1.
90. 3-[5-(4-Hydroxyphenyl)-3-thienyl]phenol (32)
##STR00098##
[0268] Synthesis: Prepared from 0.28 mmol of
4-(4-methoxyphenyl)-2-(3-methoxyphenyl)thiophene according to
method E, purification: preparative thin-layer chromatography
(hexane/ethyl acetate 5:5); yield: 80%, yellow powder; Rf
(hexane/ethyl acetate 5:5): 0.48; .sup.1H NMR (CD.sub.3OD, 500
MHz): 7.51-7.48 (m, 3H, 2Harom+1Hthiophene), 7.38 (d, J=1.20 Hz,
1H, Hthiophene), 7.20 (t, J=7.80 Hz, 1H, Harom), 7.14 (m, 1H,
Harom), 7.09 (m, 1H, Harom), 6.84 (d, J=8.80 Hz, 2H, Harom), 6.74
(1H, Harom); .sup.13C NMR (CD.sub.3OD, 125 MHz): 173.00, 158.85,
158.55, 146.50, 14.30, 138.60, 130.85, 128.40, 128.10, 127.95,
127.45, 121.85, 119.25, 118.65, 116.75, 115.15, 114.00; MS (ESI):
(M-H).sup.+: 267.
91. 3-[4-(4-Hydroxyphenyl)-2-thienyl]phenol (33)
##STR00099##
[0270] Synthesis: Prepared from 0.22 mmol of
4-(4-methoxyphenyl)-2-(3-methoxyphenyl)thiophene according to
method E, purification: preparative thin-layer chromatography
(hexane/ethyl acetate 5:5); yield: 85%, gray powder; Rf
(hexane/ethyl acetate 5:5): 0.48; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 7.56 (d, J=1.50 Hz, 1H, Hthiophene), 7.45 (d, J=8.50 Hz,
2H, Harom), 7.30 (d, J=1.50 Hz, 1H, Hthiophene), 7.10 (t, J=7.80
Hz, 1H, Harom), 7.05 (m, 2H, Harom), 6.76 (d, J=8.50 Hz, 2H,
Harom), 6.67 (m, 1H, Harom); .sup.13C NMR (CD.sub.3COCD.sub.3, 125
MHz): 158.75, 157.75, 145.40, 143.95, 136.50, 130.90, 128.35,
128.25, 123.10, 118.55, 117.75, 116.45, 116.40, 115.60, 113.30; IR:
3502, 2985, 1601, 850 cm.sup.-1; MS (ESI): (M-H).sup.+: 267.
92. 3,3'-Thiene-2,4-diyldiphenol (34)
##STR00100##
[0272] Synthesis: Prepared from 0.22 mmol of
2,4-bis(3-methoxyphenyl) thiophene according to method E,
purification: preparative thin-layer chromatography (hexane/ethyl
acetate 5:5); yield: 88%, yellow powder; Rf (hexane/ethyl acetate
5:5): 0.47; .sup.1H NMR (CD.sub.3OD, 500 MHz): 7.61 (d, J=1.50 Hz,
1H, Hthiophene), 7.46 (d, J=1.50 Hz, 1H, Hthiophene), 7.20 (m, 2H,
Harom), 7.14 (m, 2H, Harom), 7.09 (m, 2H, Harom), 6.73 (m, 2H,
Harom); .sup.13C NMR (CD.sub.3OD, 125 MHz): 158.95, 158.80, 146.05,
144.30, 138.40, 136.85, 130.95, 130.80, 123.10, 120.40, 118.55,
117.95, 115.65, 115.15, 113.55, 113.30; IR: 3480, 2925, 1652, 855
cm.sup.-1; MS (ESI): (M-H).sup.+: 267.
93. 3-Methoxybenzoic acid-N-3-(methoxybenzoyl)hydrazide
##STR00101##
[0274] Synthesis: 11.77 mmol of benzoyl chloride is dissolved in 3
drops of DMF and cooled in an ice bath. 5.88 mmol of hydrazine
monohydrate and 2 ml of triethylamine are added dropwise. After 30
min, the white precipitate is filtered off, washed with water and
dried over night in a desiccator; yield; 90%, white solid; Rf:
(hexane/ethyl acetate 1:9): 0.25; .sup.1H NMR (CD.sub.3SOCD.sub.3,
500 MHz): 10.31 (s, 2H, NH--CO), 7.53-7.42 (m, 6H, Harom), 7.16 (d,
J=8.20 Hz, 2H, Harom), 3.85 (s, 6H, OMe); .sup.13C NMR
(CD.sub.3SOCD.sub.3, 125 MHz): 159.45, 148.25, 134.30, 129.60,
119.80, 117.75, 112.95, 55.50; IR: 3252, 1709, 1695, 1453, 866
cm.sup.-1.
94. 2,5-Bis(3-methoxyphenyl)-1,3,4-oxadiazole
##STR00102##
[0276] Synthesis: 1.74 mmol of 3-methoxybenzoic
acid-N-3-(methoxybenzoyl) hydrazide, 2.09 mmol of Burgess reagent
are dissolved in 10 ml of THF and heated under microwave conditions
(100 W, 100.degree. C.) for 10 minutes. After cooling to room
temperature, the reaction mixture is washed with water, dried over
magnesium sulfate, and the THF is removed on a rotary evaporator;
yield: quantitative, white solid; Rf: (hexane/ethyl acetate 8:2):
0.65; .sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 7.75 (m, 2H,
Harom), 7.69 (m, 2H, Harom), 7.52 (t, J=7.80 Hz, 2H, Harom), 7.20
(ddd, J=1.00 Hz and J=2.50 Hz and J=7.80 Hz, 2H, Harom), 3.93 (s,
3H, OMe); .sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 165.25,
161.20, 131.35, 126.15, 119.90, 118.60, 112.65, 55.95; IR: 2920,
1515, 1254, 854 cm.sup.-1.
95. 2,5-Bis(3-methoxyphenyl)-1,3,4-thiadiazole
##STR00103##
[0278] Synthesis: 0.83 mmol of 3-methoxybenzoic
acid-N-3-(methoxybenzoyl) hydrazide and 1.67 mmol of Lawesson
reagent are dissolved in 10 ml of THF and under microwave
conditions (300 W, 90.degree. C.) for 20 minutes. After cooling to
room temperature, the reaction mixture is washed with water, dried
over magnesium sulfate and purified by column chromatography
(hexane/ethyl acetate: 8:2); yield: 70%, white-yellow solid; Rf:
(hexane/ethyl acetate 7:3): 0.52; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 7.62-7.59 (m, 4H, Harom), 7.50 (t, J=8.20 Hz, 2H, Harom),
7.15 (dd, J=2.50 Hz and J=8.20 Hz, 2H, Harom), 3.92 (s, 6H, OMe);
.sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 168.65, 161.30, 131.40,
121.15, 118.00, 113.35, 55.90; IR: 2947, 1605, 1503, 1253, 835
cm.sup.-1.
96. 3,3'-(1,3,4-Oxadiazole-2,5-diyl)diphenol (35)
##STR00104##
[0280] Synthesis: Prepared according to method E with 0.18 mmol of
2,5-bis(3-methoxyphenyl)-1,3,4-oxadiazole, purification:
preparative thin-layer chromatography (hexane/ethyl acetate 5:5);
yield: 92%, yellow solid; Rf: (hexane/ethyl acetate 5:5): 0.33;
.sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 8.87 (s, 2H, OH), 7.64
(m, 4H, Harom), 7.44 (d, J=8.20 Hz, 2H, Harom), 7.11 (ddd, J=0.90
Hz and J=2.50 Hz and J=8.20 Hz, 2H, Harom); .sup.13C NMR
(CD.sub.3COCD.sub.3, 125 MHz): 165.22, 158.90, 131.40, 126.15,
119.85, 118.85, 114.20; IR: 3450, 2925, 1615, 752 cm.sup.-1; MS
(ESI): (M-H).sup.+:253.
97. 3,3'-(1,3,4-Thiadiazole-2,5-diyl)diphenol (36)
##STR00105##
[0282] Synthesis: Prepared according to method E with 0.30 mmol of
2,5-bis(3-methoxyphenyl)-1,3,4-thiadiazole, purification:
preparative thin-layer chromatography (hexane/ethyl acetate 5:5);
yield: 82%, yellow solid; Rf: (hexane/ethyl acetate 5:5): 0.42;
.sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 8.83 (s, 2H, OHarom),
7.58 (s, 2H, Harom), 7.50 (d, J=8.20 Hz, 2H, Harom), 7.39 (t,
J=8.20 Hz, 2H, Harom), 7.05 (d, J=8.20 Hz, 2H, Harom); .sup.13C NMR
(CD.sub.3COCD.sub.3, 125 MHz): 158.95, 132.40, 131.45, 120.10,
119.25, 114.90; IR: 3399, 2854, 1612, 875 cm.sup.-1; MS (ESI):
(M-H).sup.4: 269.
98. 3-Hydroxythiobenzamide
##STR00106##
[0284] Synthesis: 4.19 mmol of 3-hydroxybenzonitrile, 4.19 mmol of
a 50% ammonium sulfite solution and 5 ml of methanol are heated
under microwave conditions (130.degree. C., 130 W, 5 bar) for 30
minutes. After cooling to room temperature, the reaction mixture is
washed with a saturated hydrogensulfite solution, dried over
magnesium sulfate and evaporated. Yield: quantitative, orange oil;
Rf: (hexane/ethyl acetate 6:4): 0.42; .sup.1H NMR
(CD.sub.3COCD.sub.3, 500 MHz): 8.93 (s, 1H), 8.76 (s, 1H), 8.58 (s,
1H), 7.49 (s, 1H, Harom), 7.41 (d, J=8.20 Hz, 1H, Harom), 7.22 (t,
J=8.20 Hz, 1H, Harom), 6.98 (dd, J=1.00 Hz and J=8.20 Hz, 1H,
Harom); .sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 156.95, 141.35,
128.95, 118.10, 117.85, 114.80; IR: 3500, 2924, 1633, 1380, 889
cm.sup.-1.
99. 3,3'-(1,2,4-Thiadiazole-2,5-diyl)diphenol (37)
##STR00107##
[0286] Synthesis: 0.17 mmol of 3-hydroxythiobenzamide and 3 ml of
concentrated hydrochloric acid are stirred in 10 ml of DMSO at room
temperature for 5 h. The reaction mixture is poured in 50 ml of
water. The precipitate formed is filtered off, washed with water
and dried over night in a desiccator. Yield: 92%, slightly
yellowish solid; Rf: (hexane/ethyl acetate 5:5): 0.33; .sup.1H NMR
(CD.sub.3COCD.sub.3, 500 MHz): 8.72 (s, 2H, OHarom), 7.87 (m, 2H,
Harom), 7.59 (m, 2H, Harom), 7.45 (t, J=7.90 Hz, 1H, Harom), 7.38
(t, J=7.90 Hz, 1H, Harom), 7.11 (d, J=8.20 Hz, 1H, Harom), 7.02 (d,
J=8.20 Hz, 1H, Harom); .sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz):
158.20, 131.70, 130.70, 129.85, 119.50, 119.25, 118.75, 117.55,
114.85, 113.65; IR: 3396, 1610, 1445, 1286, 852 cm.sup.-1; MS
(ESI): (M-H).sup.+: 269.
100. 3,5-Bis(4-methoxyphenyl)-1,2,4-thiadiazole
##STR00108##
[0288] Synthesis: 1.90 mmol of 4-methoxyphenylthiobenzamide, 1.90
mmol of 3-hydroxythiobenzamide and 1.90 mmol of concentrated
hydrochloric acid are stirred in 5 ml of DMSO at 35.degree. C. for
8 hours. Thereafter, the reaction mixture is poured in water and
the precipitate formed is filtered off, washed with water and dried
over night in a desiccator. Purification: column chromatography
(hexane/ethyl acetate 8:2); yield: 13%; Rf (hexane/ethyl acetate
8:2): 0.55; .sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 8.33 (d,
J=8.80 Hz, 2H, Harom), 8.10 (d, J=8.80 Hz, 2H, Harom), 7.16 (d,
J=8.80 Hz, 2H, Harom), 7.10 (d, J=8.80 Hz, 2H, Harom), 3.93 (s, 3H,
OMe), 3.90 (s, 3H, OMe); .sup.13C NMR (CD.sub.3COCD.sub.3, 125
MHz): 162.55, 130.60, 130.60, 130.05 (2C), 115.65 (2C), 114.90
(2C), 56.00, 55.75, IR: 2985, 1618, 1254, 854, 788 cm.sup.-1.
101. 3-[3-(4-Methoxyphenyl)-1,2,4-thiadiazole-5-yl]phenol (38)
##STR00109##
[0290] Synthesis: 1.90 mmol of 4-methoxyphenylthiobenzamide, 1.90
mmol of 3-hydroxythiobenzamide and 1.90 mmol of concentrated
hydrochloric acid are stirred in 5 ml of DMSO at 35.degree. C. for
8 hours. The reaction mixture is then poured in water, and the
precipitate formed is filtered off, washed with water and dried
over night in a desiccator. Purification: column chromatography
(hexane/ethyl acetate 8:2); yield: 30%, yellow powder; Rf
(hexane/ethyl acetate 8:2): 0.48; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.95 (s, 1H, OHarom), 8.33 (d, J=8.80 Hz, 2H, Harom),
7.88 (s.1H, Harom), 7.60 (d, J=7.60 Hz, 1H Harom), 7.44 (t, J=7.60
Hz, 1H, Harom), 7.16 (d, J=8.80 Hz, 2H, Harom), 7.11 (d, J=7.60 Hz,
1H, Harom), 3.89 (s, 3H, OMe); IR: 3452, 2932, 1632, 1242, 839
cm.sup.-1.
102. 4,4'-(1,2,4-Thiadiazole-3,5-diyl)diphenol (39)
##STR00110##
[0292] Synthesis: Prepared according to method E with 0.24 mmol of
3,5-bis(4-methoxyphenyl)-1,2,4-thiadiazole, purification:
preparative thin-layer chromatography (hexane/ethyl acetate 5:5);
yield: 92%, yellow solid; Rf (hexane/ethyl acetate 5:5): 0.33;
.sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 9.20 (s, 1H, OHarom),
8.84 (s, 1H, OHarom), 8.24 (d, J=8.50 Hz, 2H, Harom), 8.00 (d,
J=8.50 Hz, 2H Harom), 7.04 (d, J=8.50 Hz, 2H, Harom), 6.96 (d,
J=8.50 Hz, 2H, Harom); .sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz):
161.95, 130.80, 130.20, 125.95, 117.05, 116.35; IR: 3300, 1700,
1609, 837 cm.sup.-1; MS (ESI): (M-H).sup.+: 269.
103. 3-[3-(4-Hydroxyphenyl)-1,2,4-thiadiazole-5-yl]phenol (40)
##STR00111##
[0294] Synthesis: Prepared according to method E with 0.55 mmol of
3,5-bis(4-methoxyphenyl)-1,2,4-thiadiazole, purification:
preparative thin-layer chromatography (hexane/ethyl acetate 5:5);
yield: 91%, yellow oil; Rf (hexane/ethyl acetate 5:5): 0.35;
.sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 8.86 (s, 1H, OHarom),
8.82 (s, 1H, OHarom), 8.23 (d, J=8.50 Hz, 2H, Harom), 7.57 (s, 1H,
Harom), 7.54 (d, J=7.60 Hz, 1H, Harom), 7.38 (t, J=7.60 Hz, 1H,
Harom), 7.07 (d, J=7.60 Hz, 1H, Harom), 6.98 (d, J=8.50 Hz, 2H,
Harom); .sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 187.85, 159.80,
158.15, 157.70, 131.85, 131.85, 130.65, 129.95, 124.85, 114.90
(2C); IR: 3310, 1695, 1609, 852 cm.sup.-1; MS (ESI): (M-H).sup.+:
269.
104. 3-Bromo-4'-methoxybiphenyl
##STR00112##
[0296] Synthesis: Prepared according to method A with 3.18 mmol of
1,3-dibromo-benzene and 3.50 mmol of 4-methoxyphenylboronic acid,
purification: column chromatography (hexane/ethyl acetate 5%);
yield: 50%, white solid; Rf (hexane/ethyl acetate 9:1): 0.48;
.sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 7.76 (t, J=1.90 Hz,
0.1H, Harom), 7.59 (m, 3H, Harom), 7.46 (m, 1H, Harom), 7.36 (t,
J=7.90 Hz, 1H, Harom), 7.01 (d, J=8.80 Hz, 2H, Harom), 3.83 (s, 3H,
OMe); .sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 160.85, 144.00,
132.50, 131.55, 130.30, 130.05, 128.95, 126.20, 115.30, 55.70; IR:
3035, 2933, 1610, 1517, 1248, 782 cm.sup.-1.
105. 4,4''-Dimethoxy-[1,1';3',1'']terphenyl
##STR00113##
[0298] Synthesis: Prepared according to method A with 3.18 mmol of
1.3-dibromo-benzene and 3.50 mmol of 4-methoxyphenylboronic acid,
purification: column chromatography (hexane/ethyl acetate 5%);
yield: 12%, white solid; Rf: (hexane/ethyl acetate 9:1): 0.25;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 7.69 (s, 1H, Harom), 7.56 (d,
J=8.80 Hz, 4H, Harom), 7.46 (m, 3H, Harom), 6.97 (d, J=8.80 Hz, 4H,
Harom), 3.84 (s, 6H, OMe); IR: 2957, 1607, 1517, 1249, 790
cm.sup.-1.
106. 4'-Bromo-3-methoxybiphenyl
##STR00114##
[0300] Synthesis: Prepared according to method B with 3.18 mmol of
1,4-dibromo-benzene and 3.50 mmol of 3-methoxyphenylboronic acid,
purification: column chromatography (hexane/ethyl acetate 5%);
yield: 35%, white solid; Rf: (hexane/ethyl acetate 9:1): 0.50;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 7.56 (d, J=8.80 Hz, 2H, Harom),
7.45 (d, J=8.80 Hz, 2H, Harom), 7.35 (m, 1H, Harom), 7.14 (d,
J=7.60 Hz, 1H, Harom), 7.09 (s, 1H, Harom), 6.92 (dd, J=2.50 Hz,
J=8.20 Hz, 1H, Harom), 3.74 (s, 3H, OMe). IR: 3341, 2958, 1601,
1476, 1213, 777 cm.sup.-1.
107. 3,3''-Dimethoxy-[1,1';4',1'']terphenyl
##STR00115##
[0302] Synthesis: Prepared according to method B with 3.18 mmol of
1,4-dibromo-benzene and 3.50 mmol of 3-methoxyphenylboronic acid,
purification: column chromatography (hexane/ethyl acetate 5%);
yield: 14%, white solid; Rf: (hexane/ethyl acetate 9:1): 0.27;
.sup.1H NMR (CD.sub.3COCD.sub.3, 500 MHz): 7.75 (s, 4H, Harom),
7.39 (t, J=7.90 Hz, 2H, Harom), 7.28 (d, J=7.90 Hz, 2H, Harom),
7.24 (s, 2H, Harom), 6.96 (dd, J=2.50 Hz, J=8.20 Hz, 2H, Harom),
3.88 (s, 6H, OMe); .sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz):
130.80, 128.25, 119.95, 113.85, 113.20, 55.60; IR: 2925, 1581,
1479, 1221, 773 cm.sup.-1.
108. 4,3''-Dimethoxy-[1,1';3',1'']terphenyl
##STR00116##
[0304] Synthesis: Prepared according to method A with 1.33 mmol of
1.3-bromo-4'-methoxybiphenyl and 1.46 mmol of
4-methoxyphenylboronic acid, purification: column chromatography
(hexane/ethyl acetate 5%); yield: 56%, white solid; Rf:
(hexane/ethyl acetate 9:1): 0.29; .sup.1H NMR (CDCl.sub.3, 500
MHz): 7.66 (s, 1H, Harom), 7.49 (d, J=8.85 Hz, 2H, Harom), 7.43 (m,
2H, Harom), 7.37 (t, J=7.30 Hz, 1H, Harom), 7.26 (t, J=7.90 Hz, 1H,
Harom), 7.13 (d, J=9.10 Hz, 1H, Harom), 7.08 (s, 1H, Harom), 6.90
(d, J=8.80 Hz, 2H, Harom), 6.81 (d, 1H, Harom), 3.76 (s, 3H, OMe),
3.74 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3, 125 MHz): 129.80,
129.15, 128.30, 125.90, 125.80, 125.65, 119.80, 114.30, 113.05,
112.80, 55.40, 55.35; IR: 2923, 1558, 1252, 888 cm.sup.-1.
109. 4,3''-Dimethoxy-[1,1';4',1'']terphenyl
##STR00117##
[0306] Synthesis: Prepared according to method B with 1.06 mmol of
4'-bromo-3-methoxybiphenyl and 2.33 mmol of 4-methoxyphenylboronic
acid, purification: column chromatography (hexane/ethyl acetate
5%); yield: 90%, white solid; Rf: (hexane/ethyl acetate 9:1): 0.29;
.sup.1H NMR (CDCl.sub.3, 500 MHz): 7.62 (m, 4H, Harom), 7.56 (d,
J=8.80 Hz, 2H, Harom), 7.35 (t, J=7.90 Hz, 1H, Harom), 7.21 (d,
J=7.60 Hz, 1H, Harom), 7.15 (t, J=1.90 Hz, 1H, Harom), 6.98 (d,
J=8.80 Hz, 2H, Harom), 6.88 (dd, J=2.50 Hz, J=8.20 Hz, 1H, Harom),
3.10 (s, 3H, OMe), 3.79 (s, 3H, OMe); .sup.13C NMR (CDCl.sub.3, 125
MHz): 129.80, 128.05, 127.50, 127.00, 119.55, 114.30, 112.65,
55.35, 55.30; IR: 2975, 1685, 1259, 850 cm.sup.-1.
110. [1,1';3',1'']Terphenyl-4,4''-diol (41)
##STR00118##
[0308] Synthesis: Prepared according to method. E with 0.24 mmol of
4,4''-dimethoxy-[1,1';3',1'']terphenyl, purification: column
chromatography (hexane/ethyl acetate 7:3); yield: 90%, yellow
powder; Rf: (H/E 5:5): 0.52; .sup.1H NMR (CD.sub.3OD, 500 MHz):
7.66 (t, 1H, Harom), 7.94 (d, J=8.80 Hz, 4H, Harom), 7.39 (m, 3H,
Harom), 7.86 (d, J=8.50 Hz, 4H, Harom); .sup.13C NMR (CD.sub.3OD,
125 MHz): 130.10, 129.20, 125.65, 116.65; IR: 3485, 2989, 1609,
1517, 1238, 790 cm.sup.-1; MS (ESI): 261: (M-H).sup.+.
111. [1,1',4',1'']Terphenyl-3,3'-diol (42)
##STR00119##
[0310] Synthesis: Prepared according to method E with 0.24 mmol of
3,3''-dimethoxy-[1,1';4',1'']terphenyl, purification: column
chromatography (hexane/ethyl acetate 7:3); yield: 90%, yellow
powder; Rf: (H/E 5:5): 0.53; .sup.1H NMR (CD.sub.3OD, 500 MHz):
7.64 (s, 4H, Harom), 7.25 (t, J=8.20 Hz, 2H, Harom), 7.12 (d,
J=7.60 Hz, 2H, Harom), 7.07 (t, J=2.20 Hz, 2H, Harom), 6.77 (d,
J=7.90 Hz, 2H, Harom); .sup.13C NMR (CD.sub.3OD, 125 MHz): 130.90,
128.25, 119.20, 115.35, 114.65; IR: 3371, 2974, 1406, 1250, 1046,
780 cm.sup.-1; MS (ESI): 261: (M-H).sup.+.
112. [1,1';3',1'']Terphenyl-4,3''-diol (43)
##STR00120##
[0312] Synthesis: Prepared according to method E with 0.52 mmol of
4,3''-dimethoxy-[1,1';3',1'']terphenyl, purification: column
chromatography (hexane/ethyl acetate 7:3); yield: 97%, yellow
powder; Rf: (H/E 5:5): 0.52; .sup.1H NMR (CD.sub.3COCD.sub.3, 500
MHz): 8.45 (s, 1H, OHarom), 8.41 (s, 1H, OHarom), 7.78 (s, 1H,
Harom), 7.54 (m, 4H, Harom), 7.44 (t, J=7.60 Hz, 1H, Harom), 7.27
(t, J=8.20 Hz, 1H, Harom), 7.17 (d, J=8.20 Hz, 2H, Harom), 6.94 (d,
J=8.50 Hz, 2H, Harom), 6.85 (m, 1H, Harom); .sup.13C NMR
(CD.sub.3COCD.sub.3, 125 MHz): 129.90, 129.20, 128.15, 125.35,
125.00, 118.30, 115.75, 114.40, 113.90; IR: 3361, 1593, 1463, 1241,
776 cm.sup.-1; MS (ESI): 261: (M-H).sup.4.
113. [1,1';4',1'']Terphenyl-4,3''-diol (44)
##STR00121##
[0314] Synthesis: Prepared according to method E with 0.52 mmol of
4,3''-dimethoxy-[1,1';4',1'']terphenyl, purification: column
chromatography (hexane/ethyl acetate 7:3); yield: 97%, yellow
powder; Rf: (H/E 5:5): 0.52; .sup.1H NMR (CD.sub.3COCD.sub.3, 500
MHz): 8.42 (s, 1H, OHarom), 8.37 (s, 1H, OHarom), 7.62 (s, 4H,
Harom), 7.51 (d, J=8.50 Hz, 2H, Harom), 7.22 (t, J=8.20 Hz, 1H,
Harom), 7.11 (m, 2H, Harom), 6.89 (d, J=8.50 Hz, 2H, Harom), 6.70
(d, J=8.20 Hz, 1H, Harom); .sup.13C NMR (CD.sub.3COCD.sub.3, 125
MHz): 130.75, 128.75, 128.05, 127.50, 118.80, 116.65, 115.15,
114.40; IR: 3220, 1590, 1454, 1202, 780 cm.sup.-1; MS (ESI): 261:
(M-H).sup.+.
114. 4-[5-(3-Hydroxyphenyl)-2-thienyl]-2-methylphenol (45)
##STR00122##
[0316] Synthesis: Suzuki cross coupling reaction (method A)
followed by ether cleavage with boron tribromide (method E). Rf
(hexane/ethyl acetate 1:1): 0.42; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.25 (s, 1H, OH), 8.23 (s, 1H, OH), 7.44 (d, J=1.50 Hz,
1H, arom. H), 7.34 (m, 2H, arom. H), 7.25-7.22 (m, 2H, arom. H),
7.14 (m, 2H, arom. H), 6.86 (d, J=8.20 Hz, 1H, arom. H), 6.78 (dd,
J=1.50 Hz and 8.20 Hz, 1H, arom. H), 2.25 (s, 3H, CH.sub.3);
.sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 149.15, 140.90, 135.25,
131.05, 131.05, 129.35, 129.30, 127.75, 121.75, 120.35, 119.65,
117.15, 20.50; IR (neat): 3514, 2928, 2853, 1598, 798 cm.sup.-1; MS
(ESI): 281 (M-H).sup.+.
115. 4-[5-(3-Hydroxyphenyl)-2-thienyl]benzene-1,2-diol (46)
##STR00123##
[0318] Synthesis: Suzuki cross coupling reaction (method A)
followed by ether cleavage with boron tribromide (method E). Rf
(hexane/ethyl acetate 1:1): 0.12; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 7.33 (d, J=3.80 Hz, 1H, thiophene H), 7.21 (m, 2H, arom.
H), 7.17 (d, J=2.20 Hz, 1H, arom. H), 7.14 (m, 2H, arom. H), 7.06
(dd, J=8.20 Hz and J=2.20 Hz, 1H, arom. H), 6.88 (d, J=8.20 Hz, 1H,
arom. H), 6.79 (m, 1H, arom. H); .sup.13C NMR (CD.sub.3COCD.sub.3,
125 MHz): 146.40, 146.20, 144.75, 143.00, 130.95, 125.05, 123.65,
118.30, 117.50, 116.70, 115.35, 113.50, 112.90; IR (neat): 3319,
2989, 2901, 1581, 1221, 774 cm.sup.-1; MS (ESI): 283
(M-H).sup.+.
116. 2-Fluoro-4-[5-(3-hydroxyphenyl)-2-thienyl]phenol (47)
##STR00124##
[0320] Synthesis: Suzuki cross coupling reaction (method A)
followed by ether cleavage with boron tribromide (method E). Rf
(hexane/ethyl acetate 1:1): 0.48; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.86 (s, 1H, OH), 8.51 (s, 1H, OH), 7.44 (d, J=12.20 Hz,
1H, arom. H), 7.36-7.32 (m, 3H, arom. H), 7.23 (t, J=8.80 Hz, 1H,
arom. H), 7.15 (m, 2H, arom. H), 7.07 (t, J=8.80 Hz, 1H, arom. H),
6.95 (d, J=7.90 Hz, 1H, arom. H); .sup.13C NMR (CD.sub.3COCD.sub.3,
125 MHz): 158.90, 153.50, 151.60, 145.60, 145.45, 143.60, 143.10,
143.05; 136.35, 131.00, 127.70, 127.65, 125.20, 124.65, 122.80,
122.75, 119.25, 119.20, 117.60, 115.60, 114.00, 113.80, 113.00; IR
(neat): 3332, 1582, 1550, 780 cm.sup.-1; MS (ESI): 285
(M-H).sup.+.
117. 2,6-Difluoro-4-[5-(3-hydroxyphenyl)-2-thienyl]phenol (48)
##STR00125##
[0322] Synthesis: Suzuki cross coupling reaction (method A)
followed by ether cleavage with boron tribromide (method E). Rf
(hexane/ethyl acetate. 1:1): 0.41; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 7.39 (d, J=3.80 Hz, 1H, thiophene H), 7.37 (d, J=3.80 Hz,
1H, thiophene H), 7.30 (d, J=1.50 Hz, 1H, arom. H), 7.28 (d, J=1.50
Hz, arom. H), 7.22 (d, J=8.00 Hz, 1H, arom. H), 7.13 (m, 2H, arom.
H), 6.79 (m, 1H, arom. H); .sup.13C NMR (CD.sub.3COCD.sub.3, 125
MHz): 157.95, 143.55, 135.25, 130.20, 124.80, 124.45, 120.00,
116.80, 114.90, 112.20, 108.85, 108.80, 108.70, 108.65; IR (neat):
3436, 2962, 1583, 1487, 1244, 772 cm.sup.-1; MS (ESI): 303
(M-H).sup.+.
118. 4-[5-(3-Hydroxyphenyl)-2-thienyl]-2-(trifluoromethyl)phenol
(49)
##STR00126##
[0324] Synthesis: Suzuki cross coupling reaction (method A)
followed by ether cleavage with boron tribromide (method E). Rf
(hexane/ethyl acetate 1:1): 0.47; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 7.71 (d, J=2.30 Hz, 1H, arom. H), 7.66 (dd, J=8.50 Hz and
J=J=2.30 Hz, 1H, arom. H), 729 (m, 2H, arom. H), 7.14 (t, J=7.90
Hz, 1H, arom. H), 7.06-7.03 (m, 3H, arom. H), 6.67 (m, 1H, arom.
H); .sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 158.90, 143.90,
136.70, 131.40, 131.0, 125.30, 124.90, 118.70, 117.60, 115.70,
113.05; IR (neat): 3491, 3387, 1583, 1490, 799 cm.sup.-1; MS (ESI):
285 (M-H).sup.+.
120. 3-[5-(3-Fluorophenyl)-2-thienyl]phenol (50)
##STR00127##
[0326] Synthesis: Suzuki cross coupling reaction (method A)
followed by ether cleavage with boron tribromide (method E). Rf
(hexane/ethyl acetate 6:4): 0.52; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.20 (s, 1H, OH), 7.39 (m, 2H, arom. H), 7.34-7.29 (m,
3H, arom. H), 7.13 (t, J=7.90 Hz, 1H, arom. H), 7.06 (s, 1H, arom.
H), 7.04 (s, 1H, arom. H), 6.95 (m, 1H, arom. 1H), 6.71 (m, 1H,
arom. H); .sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 163.10,
158.85, 145.15, 142.30, 137.40, 137.35, 136.10, 131.90, 131.10,
126.30, 125.40, 122.20, 117.70, 115.90, 115.05, 114.90, 113.15,
112.75, 112.60; IR (neat): 2989, 2901, 1580, 1242, 1057, 775
cm.sup.-1; MS (ESI): 269 (M-H).sup.+.
121. N-{3-[5-(3-Hydroxyphenyl)-2-thienyl]phenyl}methanesulfonamide
(51)
##STR00128##
[0328] Synthesis: Suzuki cross coupling reaction (method A)
followed by ether cleavage with boron tribromide (method E). Rf
(hexane/ethyl acetate 4:6): 0.42; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.68 (s, 1H), 8.53 (s, 1H), 7.67 (s, 1H, arom. H), 7.47
(d, J=8.20 Hz, 1H, arom. H), 7.42 (m, 3H, arom. H), 7.31 (d, J=8.80
Hz, 1H, arom. H), 7.25 (t, J=7.90 Hz, 1H, arom. H), 7.17 (m, 2H,
arom. H), 6.83 (d, J=8.20 Hz, 1H, arom. H) 3.05 (s, 3H, CH.sub.3);
.sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 160.00, 143.60, 142.65,
135.30, 130.15, 130.10, 129.30, 124.85, 124.75, 124.30, 121.20,
120.20, 119.15, 117.85, 116.85, 112.95, 110.80, 32.00; IR (neat):
3279, 1587, 1470, 1142, 783 cm.sup.-1; MS (ESI): 344
(M-H).sup.+.
122. 3-(5-Phenyl-2-thienyl)phenol (52)
##STR00129##
[0330] Synthesis: Suzuki cross coupling reaction (method A)
followed by ether cleavage with boron tribromide (method E). Rf
(hexane/ethyl acetate 7:3): 0.62; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.51 (s, 1H, OH), 7.70 (d, J=8.50 Hz, 2H, arom. H),
7.44-7.42 (m, 4H, arom. H), 7.30 (t, J=7.20 Hz, 1H, arom. H), 7.19
(t, J=7.25 Hz, 1H, arom. H), 7.18 (m, 2H, arom. H), 6.80 (d, J=7.80
Hz, 1H, arom. H); .sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz):
158.85, 114.30, 144.00, 136.35, 135.05, 131.05, 129.95, 129.95,
128.50, 126.25, 126.25, 125.30, 125.25, 117.65, 115.70, 113.05; IR
(neat): 3416, 1582, 1442, 1180, 752 cm.sup.-1; MS (ESI): 351
(M-H).sup.+.
123. 3-[5-(4-Hydroxyphenyl)-2-thienyl]-5-methylphenol (53)
##STR00130##
[0332] Synthesis: Suzuki cross coupling reaction (method A)
followed by ether cleavage with boron tribromide (method E). Rf
(hexane/ethyl acetate 1:1): 0.42; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.57 (s, 1H, OH), 8.36 (s, 1H, OH), 7.51 (d, J=8.50 Hz,
2H, arom. H), 7.29 (d, J=3.60 Hz, 1H, thiophene H), 7.21 (d, J=3.60
Hz, 1H, thiophene. H), 6.96 (s, 1H, arom. H), 6.92 (s, 1H, arom.
H), 6.88 (d, J=8.50 Hz, 2H, arom. H), 6.60 (s, 1H, arom. H), 2.26
(s, 3H, CH.sub.3aliphatic); .sup.13C NMR (CD.sub.3COCD.sub.3, 125
MHz): 157.85, 157.35, 143.45, 142.05, 139.95, 135.40, 126.85,
126.80, 125.95, 124.05, 122.65, 117.45, 115.85, 115.25, 109.30,
20.55; IR (neat): 3308, 2948, 1593, 1220, 827 cm.sup.-1; MS (ESI):
281 (M-H).sup.+.
124. 3-[5-(4-Fluorophenyl)-2-thienyl]phenol (54)
##STR00131##
[0334] Synthesis: Suzuki cross coupling reaction (method A)
followed by ether cleavage with boron tribromide (method E). Rf
(hexane/ethyl acetate 1:1): 0.74; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.48 (s, 1H, OH), 7.75-7.72 (m, 2H, arom. H), 7.40 (m,
2H, arom. H), 7.25-7.16 (m, 5H, arom. H), 6.81 (m, 1H, arom. H);
.sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 135.50, 133.15, 127.15,
126.55, 120.10, 117.45; IR (neat): 3482, 2925, 1585, 799 cm.sup.-1;
MS (ESI): 269 (M-H).sup.+.
125. 4-[5-(3-Hydroxyphenyl)-3-thienyl]-2-methylphenol (55)
##STR00132##
[0336] Synthesis: Suzuki cross coupling reaction (method A)
followed by ether cleavage with boron tribromide (method E). Rf
(hexane/ethyl acetate 1:1): 0.42; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.49 (s, 1H, OH), 8.30 (s, 1H, OH), 7.73 (s, 1H, arom.
H), 7.52 (s, 1H, arom. H), 7.46 (s, 1H, arom. H), 7.42 (d, J=8.20
Hz, 1H, arom. H), 7.22-7.19 (m, 3H, arom. H), 6.87 (d, J=8.20 Hz,
1H, arom. H), 6.81 (m, 1H, arom. H), 2.25 (s, 3H, CH.sub.3);
.sup.13C NMR (CD.sub.3COCD.sub.3, 125 MHz): 170.95, 158.80, 155.85,
145.25, 144.10, 136.70, 130.95, 129.65, 128.30, 125.50, 125.40,
123.20, 118.40, 117.75, 115.85, 115.55, 113.24, 16.30; IR (neat):
3288, 2916, 1600, 782 cm.sup.-1; MS (ESI): 281 (M-H).sup.+.
126. 4-[2-(3-Hydroxyphenyl)-1,3-thiazole-5-yl]-2-methylphenol
(56)
##STR00133##
[0338] Synthesis: Suzuki cross coupling reaction (method A)
followed by ether cleavage with boron tribromide (method E). Rf
(hexane/ethyl acetate 1:1): 0.55; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 7.97 (s, 1H, arom. H), 7.49 (s, 1H, arom. H), 7.45 (m,
2H, arom. H), 7.32 (m, 1H, arom. H), 7.30 (t, J=8.20 Hz, 1H arom.
H), 6.90 (m, 2H, arom. H), 2.25 (s, 3H, CH.sub.3); .sup.13C NMR
(CD.sub.3COCD.sub.3, 125 MHz): 170.95, 158.80, 155.85, 145.25,
144.10, 136.70, 130.95, 129.65, 128.30, 125.50, 125.10, 123.20,
118.40, 117.75, 115.85, 115.55, 113.24, 16.30; IR (neat): 3300,
2906, 1572, 1222, 817 cm.sup.-1; MS (ESI): 281 (M-H).
127. 3,3'-Pyridine-2,5-diyldiphenol (57)
##STR00134##
[0340] Synthesis: Suzuki cross coupling reaction (method A)
followed by ether cleavage with boron tribromide (method E). Rf
(hexane/ethyl acetate 1:1): 0.46; .sup.1H-NMR (500 MHz,
CD.sub.3COCD.sub.3): 8.91 (dd, J=0.90 Hz, J=2.5 Hz, 1H, arom. H)
8.63 (s, 2H, OH), 8.04 (dd, J=8.20 Hz, J=2.20 Hz, 1H, arom. H),
7.92 (d, J=8.20 Hz, 1H, arom. H), 7.71 (t, J=2.50 Hz, 1H, arom. H),
7.61 (d, J=7.60 Hz, 1H, arom. H), 7.30-7.35 (m, 2H, Arom. H),
7.20-7.21 (m, 2H, arom. H), 6.91-6.96 (m, 2H, arom. H).
.sup.13C-NMR (125 MHz, CD.sub.3COCD.sub.3): 159.00, 158.80, 156.45,
148.50, 141.25, 139.80, 135.80, 135.70, 131.15, 130.65, 120.95,
118.95, 118.80, 116.95, 116.05, 114.50, 114.45. IR (neat) 3258,
1692, 1586, 1207, 781 cm.sup.-1. MS (ESI): 263 (M-H).sup.+.
128. 3,3'-Pyrazine-2,5-diyldiphenol (58)
##STR00135##
[0342] Synthesis: Suzuki cross coupling reaction (method A)
followed by ether cleavage with boron tribromide (method E). Rf:
(hexane/ethyl acetate 1:1): 0.31; .sup.1H NMR (CD.sub.3COCD.sub.3,
500 MHz): 8.93 (s, 1H, arom. H), 8.92 (s, 1H, arom. H), 8.79 (s,
1H, arom. H), 7.61 (m, 2H, arom. H), 7.38 (t, J=7.90 Hz, 1H, arom.
H), 7.01 (dd, J=7.90 Hz and J=2.00 Hz, 1H, arom. H); .sup.13C NMR
(CD.sub.3COCD.sub.3, 125 MHz): 146.55, 142.00, 130.20, 117.95,
117.30, 113.60; IR (neat): 3321, 2959, 1607, 1456, 810 cm.sup.-1;
MS (ESI): 263 (M-H).sup.+.
127. 3,3'-(1,2,4,5-Tetrazine-3,6-diyl)diphenol (59)
##STR00136##
[0344] Synthesis: To a stirred mixture of 3-hydroxybenzonitrile
(1.0 g, 8.4 mmol) and sulfur powder (135 mg, 4.2 mmol) in a few ml
of ethanol, hydrazine monohydrate (0.8 ml, 16.8 mmol) is added,
followed by heating under reflux for 2 h. After cooling to room
temperature, sodium nitrite (926 mg) is added, followed by heating
at 50.degree. C. for another 2 h. The resulting suspension is
filtered, and the solid is purified by column chromatography.
Yield: 49 mg (6%), red solid. Rf (hexane/ethyl acetate 1:1): 0.57;
.sup.1H-NMR (500 MHz, CD.sub.3COCD.sub.3): 7.36 (m, 2H, arom. H),
7.14-7.20 (m, 6H, arom. H); .sup.13C-NMR (125 MHz,
CD.sub.3COCD.sub.3): 158.70, 131.60, 124.10, 121.40, 119.40,
119.25, 113.85. IR (neat): 3362, 2239, 1583, 1283, 784, 678
cm.sup.-1; MS (ESI): 265 (M-H).sup.+.
Example 2
[0345] Determination of the inhibitory activity of the potential
inhibitors: Inhibition of 17.beta.-HSD1 and 17.beta.-HSD2: In both
cases, human placenta served as the enzyme source (Lin, S.-X. et
al., J. Biol. Chem., 267: 16182-16187 (1992)).
[0346] In the 17.beta.-HSD1 test, NADH is employed as a cosubstrate
at a final concentration of 500 .mu.M in order to avoid the product
inhibition occurring with NADPH. The enzyme preparation is diluted
with test buffer to such an extent that the control conversion is
10 to maximally 20% (about 1:650). As the substrate, estrone in a
final concentration of 500 nM is used, of which 3 nM is tritiated.
2,4,6,7-[.sup.3H]estrone is purchased from Perkin-Elmer, Boston.
The inhibitor is added as a solution in DMSO (control: pure DMSO
without inhibitor; the final concentration of DMSO in the assay is
1% in all cases). After the addition of the substrate, incubation
is performed at 37.degree. C. for 10 minutes, followed by quenching
by the addition of HgCl.sub.2 (final concentration of HgCl.sub.2:
1.66 mM).
[0347] In the 17.beta.-HSD2 test, the natural cosubstrate NAD.sup.+
is employed at a final concentration of 1500 .mu.M. The microsome
fraction is diluted in test buffer, so that a control conversion of
20 to 30% results (about 1:350). As the substrate, estradiol in a
final concentration of 500 nM is used, of which 3 nM is tritiated.
2,4,6,7-[.sup.3H]estradiol is also purchased from Perkin-Elmer,
Boston. The inhibitor is added as a solution in DMSO (control: pure
DMSO without inhibitor; the final concentration of DMSO in the
assay is 1 in all cases). After the addition of the substrate,
incubation is performed at 37.degree. C. for 20 minutes. The
reaction is quenched by the addition of HgCl.sub.2 (final
concentration of HgCl.sub.2: 0.166 mM).
[0348] After the reaction, the substrate and product are extracted
by partitioning with ether, separated by chromatography (HPLC) and
quantified by means of radiodetection. Compounds (1)-(7), (9)-(17),
(21), (24)-(25), (27), (30), (35) and (39) do not show any
inhibition of 17.beta.-HSD1 at a concentration of 1 .mu.M. Compound
(24) shows 49% inhibition at 1 .mu.M 17.beta.-HSD1. The inhibitory
activities of further compounds are expressed as IC.sub.50 values
and are summarized in Table 1.
TABLE-US-00001 TABLE 1 Inhibition of 17.beta.-HSD1 and -HSD2
Selectivity 17.beta.-HSD1 17.beta.-HSD2 IC.sub.50 (17.beta.-HSD2)/
Compound IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (17.beta.-HSD1) 8
570 1020 1.8 18 560 800 1.4 19 50 4000 80 20 180 3100 17 22 280
2500 8.9 23 320 n.d. -- 26 410 2220 5.4 28 3400 1800 0.5 29 60 1950
33 31 110 750 6.8 32 130 1700 13 33 70 1270 18 34 170 560 3.3 36
510 n.d. -- 37 180 600 3.3 38 820 n.d. -- 40 360 2200 6.1 41 1600
2200 1.4 42 110 2300 21 43 1410 3100 2.2 44 240 4500 19 45 40 1970
49 46 800 1640 2.1 47 10 940 94 48 50 230 4.6 49 40 n.d. -- 50 530
n.d. -- 51 520 n.d. -- 52 340 2340 6.9 53 450 n.d. -- 54 720 n.d.
-- 55 100 870 8.7 56 100 2020 20 57 100 3400 34 58 1000 5500 5.5 59
200 5100 26 n.d. = not determined
[0349] Affinity for the estrogen receptor .alpha.: The affinities
of the inhibitors for estrogen receptor .alpha. were determined
according to the method described by Zimmermann et al. (Zimmermann,
J. et al., J. Steroid Biochem. Mol. Biol., 94: 57-66 (2005)).
Slight changes were made: The respective inhibitor was incubated at
RT for 2 h with shaking. After the addition of hydroxyapatite, the
mixture was stored on ice for 15 min and vortexed every 5 min.
[0350] The receptor affinities are established as RBA (relative
binding affinity) values. The RBA value of the reference estradiol
is set to 100%. The inhibitors (19), (22), (31), (37), (47), (48),
(49), (52), (55) and (57) were examined. In all cases, the RBA
values are below 0.1%.
[0351] Drug interactions (inhibition of hepatic CYP enzymes): The
inhibition of six human hepatic cytochrome P450 enzymes by selected
compounds was examined by means of the kit supplied by Becton
Dickinson GmbH (Heidelberg). The data are summarized in Table
2.
TABLE-US-00002 TABLE 2 Inhibition of hepatic CYP enzymes IC50 (mean
.+-. SD) [.mu.M] Compound CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6
CYP3A4 22 4.92 .+-. 0.09 14.22 .+-. 0.44 0.790 .+-. 0.018 4.57 .+-.
0.05 7.76 .+-. 0.03 1.95 .+-. 0.01 28 5.35 .+-. 0.24 18.82 .+-.
2.05 2.98 .+-. 0.02 3.37 .+-. 0.12 6.99 .+-. 0.02 7.36 .+-. 0.49 32
8.68 .+-. 0.29 11.21 .+-. 0.64 2.10 .+-. 0.09 4.43 .+-. 0.17 37.58
.+-. 1.00 0.84 .+-. 0.036 42 17.20 .+-. 1.16 7.68 .+-. 0.92 1.94
.+-. 0.10 4.20 .+-. 0.29 22.03 .+-. 0.29 2.13 .+-. 0.13 Positive
control Furafyllin Tranylcypromin Sulfaphenazole Tranylcypromine
Quinidine Ketoconazole IC.sub.50 [.mu.M] 3.04 .+-. 0.08 6.96 .+-.
0.025 0.250 .+-. 0.027 3.04 .+-. 0.17 0.011 .+-. 0.001 0.054 .+-.
0.001
[0352] Performance of selected compounds in a CaCo2 assay: Caco-2
cell culture and transport experiments were performed according to
Yee (Yee, S., Pharm. Res., 14(6): 763-766 (1997)), but slight
modifications were introduced. The cultivation times were reduced
from 21 to 10 days by increasing the sowing density from
6.310.sup.4 to 1.6510.sup.5 cells per well. Four reference
compounds (atenolol, testosterone, ketoprofene and erythromycin)
were employed in each assay for evaluating the transport properties
of the CaCo-2 cells. The initial concentration of the compounds in
the donor compartment was 50 .mu.M (in buffer with 1% ethanol or
DMSO). Samples were taken from the acceptor side after 60, 120 and
180 min and from the donor side after 0 and 180 min. For
glycoprotein P (P-gp) studies, bidirectional experiments were
performed. The absorptive and secretory permeabilities (P.sub.app
(a-b) and P.sub.app (b-a)) were determined. Thus, erythromycin was
used as a substrate, and verapamil was used as an inhibitor of
P-gp. Each experiment was performed in triplicate. The integrity of
the monolayer was determined by means of TEER (transepithelial
electric resistance) and the permeability for each assay was
determined using Lucifer Yellow. All samples of the CaCo-2
transport experiments were analyzed by means of LC/MS/MS after
dilution with buffer (1:1 with 2% acetic acid). The apparent
permeability coefficient (P.sub.app) was calculated by means of the
formula given below, where dQ/dt represents the recovery rate of
the mass in the acceptor compartment, A represents the surface area
of the transwell membrane, and c.sub.0 represents the initial
concentration in the donor compartment. The data for selected
inhibitors are summarized in Table 3.
P app = Q t A c 0 ##EQU00001##
TABLE-US-00003 TABLE 3 P.sub.app Compound [cm/sec .+-. rel. SD]
Permeability 8 (7.9 .+-. 0.8) 10.sup.-6 medium-high 18 (7.3 .+-.
0.9) 10.sup.-6 medium-high 19 (7.8 .+-. 2.5) 10.sup.-6 medium-high
20 (11.7 .+-. 8.1) 10.sup.-6 high 28 (11.5 .+-. 7.7) 10.sup.-6 high
29 (22.0 .+-. 1.0) 10.sup.-6 high 32 (14.4 .+-. 8.3) 10.sup.-6 high
37 (3.6 .+-. 0.5) 10.sup.-6 medium 41 (12.6 .+-. 7.2) 10.sup.-6
high 42 (12.5 .+-. 9.0) 10.sup.-6 high 53 (24.2 .+-. 6.9) 10.sup.-6
high
[0353] Test for metabolic stability (rat liver microsomes): The
stock solutions (10 mM in acetonitrile (AcCN)) are diluted to
obtain working concentrations in 20% AcCN which are 10 times higher
than the incubation concentrations of the compounds.
[0354] The incubation solution (180 .mu.l) consists of 90 .mu.l of
a microsomal suspension of 0.33 mg/ml protein in 100 mM phosphate
buffer, pH 7.4, with 90 .mu.l NADP.sup.+-regenerating system
(NADP.sup.+: 1 mM, glucose-6-phosphate 5 mM, glucose-6-phosphate
dehydrogenase: 5 U/ml, MgCl.sub.2 5 mM).
[0355] The reaction is started by adding 20 .mu.l of the compound
to be tested in 20% AcCN to the microsome/buffer mixture
preincubated at 37.degree. C. After 0, 15, 30 and 60 minutes, 200
.mu.l of sample solution is withdrawn and subjected to AcCN
precipitation. The isolation of the compounds is effected by adding
200 .mu.l of AcCN that contains the internal standard (1 .mu.M) to
200 .mu.l of sample solution and calibration standard. After
shaking for 10 s and centrifugation at 4000 g, an aliquot of the
supernatant is subjected to LC-MS/MS. Two controls are included: a
positive control with 7-ethoxycoumarin as a reference to verify the
microsomal enzyme activity, and a negative control in which
microsomes are used that were heated for 25 minutes without a
regenerating system, in order to ensure that the loss of substance
is actually due to metabolization.
[0356] The amount of compound in a sample is expressed as the
percent fraction of the compound remaining as compared to time t=0
(100%). The percent fraction is plotted versus time.
[0357] The thus established half lives of selected inhibitors and
of the reference substances diazepam and diphenhydramine are
summarized in Table 4.
TABLE-US-00004 TABLE 4 Compound Half life [min] 22 12.6 28 10.6 32
18.6 42 22.7 Diazepam 40.77 Diphenhydramine 6.80
[0358] In vivo pharmacokinetics (rat): The compounds 29, 45, 47 and
59 and a reference compound were administered to adult male Wistar
rats (n=4) perorally in a cassette dosing method (vehicle:
Labrasol/water 1/1). The plasma profiles were established by means
of LC-MS/MS. The data obtained are summarized in Table 5.
TABLE-US-00005 TABLE 5 Compound internal Parameter reference 29 45
47 59 Dose (mg/kg) 10 10 10 10 10 C.sub.max obs (ng/kg) 43.2 7.8
905.0 1388.2 106.0 C.sub.z (ng/kg) 0.38 6.56 43.35 24.97 54.03
t.sub.max obs (h) 2.0 8.0 4.0 8.0 3.0 t.sub.z (h) 24.0 10.0 24.0
24.0 10.0 t.sub.1/2z (h) 2.4 1.5 3.8 2.7 1.2 AUC.sub.0-tz (ng h/ml)
539.0 99.2 12037.3 19310.9 1204.5 AUC.sub.0-.infin. (ng h/ml) 540.3
99.2 12275.4 19407.1 1204.5
[0359] C.sub.max obs highest measured concentration [0360] C.sub.z
last analytically quantifiable concentration [0361] t.sub.max obs
time to reach the highest measured concentration [0362] t.sub.z
time to withdrawal of the last sample with analytically
quantifiable concentration [0363] t.sub.1/2z half life (determined
from the slope of the declining portion of the concentration vs.
time curve [0364] AUC.sub.0-tz area below the concentration vs.
time curve up to time t.sub.Z [0365] AUC.sub.0-.infin. area below
the concentration vs. time curve, extrapolated to .infin.
[0366] Comparison of the inhibition data for isomeric
bis(hydroxyphenyl)-1,3-thiazoles: When isomeric thiazoles are
compared, only the para-/meta- or meta-/meta-substituted thiazoles
show an inhibition of 17.beta.-HSD1, while the
para-/para-substituted compound 25, which is the sole of this
series to be mentioned as an example in WO 00/19994, shows no
activity (see Table 6). The affinities of the potent inhibitors 23,
24 and 26 for the estrogen receptor are negligible (data not
stated).
TABLE-US-00006 TABLE 6 Inhibition of RBA (%) Compound No.
17.beta.-HSD1, (Katzenellenbogen HSD patent Structure IC.sub.50
(nM) patent) 23 ##STR00137## 320 not described 24 ##STR00138## 49%
inhibition at 1 mM not described 25 ##STR00139## no inhibition
0.018 26 ##STR00140## 410 not described
* * * * *